Research Models
Parkinson's Disease
Progress in Parkinson's disease research and therapeutic development depends on robust preclinical models, including rodent models. By organizing information related to the characterization of selected PD models, this resource conveys what is known about each one and facilitates comparison of phenotypes. This resource was created in collaboration with The Michael J. Fox Foundation (MJFF) as part of its commitment to make PD models more accessible and accelerate PD research.
The Parkinson's disease models were selected by experts at The Michael J. Fox Foundation (MJFF).
30 Models
30 Visualizations
Phenotypes Examined
- Neuronal Loss
- Dopamine Deficiency
- α-synuclein Inclusions
- Neuroinflammation
- Mitochondrial Abnormalities
- Motor Impairment
- Non-Motor Impairment
When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.
DJ-1 KO Rat
Observed
-
Non-Motor Impairment at 17
Olfactory detection enhanced (16 mos). Short-term memory abnormal (4.5, 15 mos). Appetitive instrumental learning normal (4, 6, 8 mos). Coping behavior (forced-swim test) impaired (6 mos). No anxiety-like behavior (elevated plus maze; 4, 8, 17 mos), less anxiety on light-dark box (6, 8 mos). No sucrose preference at 9 mos. Sensorimotor function (adhesive removal) unaffected (4, 7, 13 mos).
-
Motor Impairment at 17
Abnormalities in gait and strength, vocalizations, and tongue movements were observed. By 4 months, the rats exhibited abnormal paw positioning and a shorter stride. Males showed impaired licking, longer and more frequent ultrasonic vocalizations, and an accelerated decrease in average call intensity with age. Fine motor skills were also impaired in KO versus wild-type rats by 7 months of age.
-
Mitochondrial Abnormalities at 13
At 3 months of age, the mitochondrial proteome in DJ-1 KO rats was differentially expressed compared to wild-type rats. Mitochondrial respiration was also increased in KO versus wild-type rats
-
Neuronal Loss at 26
Age-related decreases in TH-positive dopaminergic neurons were reported in the substantia nigra and locus coeruleus reaching approximately 50 percent by 8 months of age. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum.
Absent
-
Dopamine Deficiency at
Striatal dopamine level was increased 2-3 fold in KO rats compared to wild-type levels at 8 months of age. Dopaminergic innervation of the dorsal striatum was intact in DJ-1 KO rats at 4 and 6 months of age compared to wild-type rats. Basal levels of dopamine metabolites and evoked levels of dopamine in the striatum were not different between KO and wild-type rats.
-
α-synuclein Inclusions at
Staining for α-synuclein revealed no increase in the striatum or in any other brain region assessed.
No Data
-
Neuroinflammation at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Park7 (DJ1) | Park7 (DJ1): Knock-Out | Parkinson's Disease | Age-related decrease in dopaminergic neurons in the substantia nigra and locus coeruleus; approximately 50 percent reduction by 8 months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum. |
Enhanced olfactory detection, abnormal short-term memory, impaired coping behavior, reduced anxiety on light-dark box. Abnormalities in gait, paw positioning, strength, vocalizations, and tongue movements. In males, impaired licking, longer and more frequent ultrasonic vocalizations, and accelerated decrease in average call intensity with age. |
Gba1 D409V KI Mouse (Grabowski)
Observed
-
Non-Motor Impairment at 17
Memory is impaired starting at 4 months in homozygous KI mice based on the novel object recognition and contextual fear-conditioning tests. In D409V/null mice, memory was impaired at 9 months; heterozygous KI mice did not exhibit memory deficits at 6 months. Anxiety- and compulsive-like behaviors were perturbed in D409V/null mice at 6 months, based on the marble burying test.
-
α-synuclein Inclusions at 18
Progressive α-synuclein accumulation starting at 6 months of age in homozygous and heterozygous KI mice as well as in D409V/null mice, and may be present even as early as 4 months of age, in the forebrain and hippocampus.
-
Motor Impairment at 14
Homozygous KI mice do not exhibit gait abnormalities or locomotion based on the open-field test, at 8 and 12 months, respectively. However, D409V/null mice exhibit perturbances in gait as early as 3 months of age.
Absent
-
Neuroinflammation at
No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining.
-
Neuronal Loss at
No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age.
No Data
-
Dopamine Deficiency at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Gba1 | Gba1: Knock-In | Parkinson's Disease | No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age. No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining. Progressive α-synuclein accumulation starting as early as 4 months of age in the forebrain and hippocampus. |
Memory impaired starting at 4 months in homozygous KI mice and at 9 months in D409V/null mice. Anxiety- and compulsive-like behaviors perturbed in D409V/null mice at 6 months. Gait and locomotion normal in homozygous KI mice at 8 and 12 months, but impaired gait in D409V/null mice as early as 3 months. |
Gba1 D409V KI Mouse (MJFF)
Observed
-
Dopamine Deficiency at 55
Dopamine levels did not differ at 4, 8, and 12 months of age, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase, though the increase was only significant at 12 months of age.
-
Non-Motor Impairment at 54
Cognitive performance was impaired in 12-month-old heterozygous KI mice (but not at 3, 6, or 9 months), based on the Morris water maze and Y-maze. Anxiety-like behavior (based on the open-field test) did not differ at 12 months.
-
α-synuclein Inclusions at 54
Homozygous KI mice have higher levels of soluble monomeric α-synuclein in the hippocampus at 12 months than heterozygous KI mice and wild-type controls. Levels of pathologic phosphorylated form pS129 do not differ between homozygous KI mice and controls in the substantia nigra, cortex, or hippocampus.
-
Neuroinflammation at 54
Data are mixed on levels of GFAP and Iba-1 immunostaining in KI mice brain. One study in homozygous KI mice found no differences in the striatum and substantia nigra at 4, 8, or 12 months of age; another found decreased GFAP staining in the substantia nigra at 12 months; and a third study (het mice) found increased GFAP and Iba-1 in the hippocampus at 12 months.
-
Motor Impairment at 36
Homozygous D409V KI mice generally exhibit motor function similar to wild-type controls (open-field, Rotarod, grip strength, swim velocity). However, a couple of exceptions found in one study were greater grip strength force at 12 months of age and transiently increased locomotor activity on the open-field test at 8 months of age.
Absent
-
Neuronal Loss at
No differences in the number of dopaminergic neurons in the substantia nigra pars compacta were found between homozygous KI mice and wild-type mice at 4, 8, and 12 months of age.
No Data
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Gba1 | Gba1: Knock-In | Parkinson's Disease | No deficits in dopaminergic neuron numbers in the substantia nigra pars compacta between homozygous KI mice and wild-type mice. Dopamine levels did not differ, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase at older ages. Mixed findings on GFAP and Iba-1 staining across brain regions in KI mice. |
Motor function is largely intact in KI mice, apart from transient increases in locomotor activity and increased grip strength at 8 and 12 months, respectively. Cognitive performance was impaired at 12 months of age, but not at younger ages. Anxiety-like behavior was not affected. |
Gba1 L444P KI Mouse (JAX)
Observed
-
α-synuclein Inclusions at 52
α-synuclein deposition reported in the striatum of 1-year-old mice in one study, but no differences in α-synuclein levels found in brain extracts of 6- and 14-month-old KI mice in another study.
-
Neuroinflammation at 53
Increased GFAP immunoreactivity observed in the striatum of 1-year-old mice in one study, but no differences in striatal GFAP or Iba-1 immunostaining observed in another study of 14-month-old KI mice.
Absent
-
Motor Impairment at
No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice.
-
Neuronal Loss at
No loss in dopaminergic cell numbers in the substantia nigra at 14 months of age.
No Data
-
Dopamine Deficiency at
No data.
-
Non-Motor Impairment at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Gba1 | Gba1: Knock-In | Parkinson's Disease | No loss of dopaminergic cells in the substantia nigra at 14 months. Inconsistent results regarding α-synuclein deposition and striatal GFAP immunostaining. |
No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice. |
Gba1 L444P KI Mouse (MMRRC)
Observed
-
Non-Motor Impairment at 13
Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice. No deficits in olfaction (buried pellet test) or on the novel object recognition test at 24 months of age.
-
Neuroinflammation at 104
GFAP staining was comparable in heterozygous KI and wild-type mice at 8 and 24 months of age. Iba1 staining, however, was increased in 24-month-old heterozygous KI mice, but only in the granule cell layer of the olfactory bulb.
-
Mitochondrial Abnormalities at 35
By 8 months of age, heterozygous KI mice have impaired mitochondrial structure (smaller) and function (lower levels of mitochondrial DNA) in the midbrain. Mitochondrial function from cultured cortical neurons also impaired (increased reactive oxygen species generation, decreased mitochondrial complex I enzyme activity, decreased oxygen consumption rate).
Absent
-
Dopamine Deficiency at
Levels of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), HVA (homovanillic acid), or their ratio (to assess dopamine turnover) were similar in saline-treated heterozygous KI and wild-type mice at 8 months of age.
-
α-synuclein Inclusions at
α-synuclein levels are increased in the ventral midbrain in heterozygous L444P KI mice at 8 months, as well as in other brain regions assessed at 24 months. Another study, however, reported no differences in total synuclein levels at 3 months, but a decrease in soluble phosphorylated α-synuclein. There is no evidence of α-synuclein aggregates in this model.
-
Motor Impairment at
No differences between heterozygous KI and wild-type mice in open-field test performance at 3 months. At 8 months, heterozygous KI mice also performed at similar levels to wild-type controls on pole and grip strength tests. Heterozygous KI mice may perform better on the pole test at younger (3 months) ages. Pole test performance was also similar between genotypes at 24 months of age.
-
Neuronal Loss at
No deficits in the number of TH-positive neurons in the substantia nigra pars compacta or in the density of TH-immunopositive fibers in the striatum in 8-month-old heterozygous L444P KI mice.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Gba1 | Gba1: Knock-In | Parkinson's Disease | Dopaminergic neuron numbers are intact in the substantia nigra. Some alterations in soluble α-synuclein levels, but no findings of aggregation. Levels of dopamine and its metabolites are not perturbed in heterozygous KI mice. Neuroinflammation as measured by GFAP is not observed in heterozygous KI mice, but Iba1 staining may be increased in some regions. |
Largely no differences in motor function between heterozygous KI and wild-type mice from 3 to 24 months of age. Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice, but no deficits in olfaction or on the novel object recognition test at 24 months of age. |
HGBA L444P Tg on Gba1 KO Mouse
Observed
Absent
-
α-synuclein Inclusions at
Older HGBA L444P /Gba−/− mice do not show evidence of α-synuclein inclusions.
-
Motor Impairment at
No obvious phenotypic features noted.
-
Neuronal Loss at
Older HGBA N370S/Gba−/− mice do not show evidence of neuropathology.
No Data
-
Dopamine Deficiency at
-
Non-Motor Impairment at
-
Neuroinflammation at
-
Mitochondrial Abnormalities at
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
GBA1, Gba1 | GBA1: Transgenic; Gba1: Knock-Out | Parkinson's Disease | Older mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system glucosylsphingosine, but not glucosylceramide, were noted. |
No obvious phenotypic features noted. |
HGBA N370S Tg on Gba1 KO Mouse
Observed
Absent
-
α-synuclein Inclusions at
Older HGBA N370S/Gba−/− mice do not show evidence of α-synuclein inclusions.
-
Motor Impairment at
No obvious features noted.
-
Neuronal Loss at
Neuronal Loss Older HGBA N370S/Gba−/− mice do not show evidence of neuropathology.
No Data
-
Dopamine Deficiency at
-
Non-Motor Impairment at
-
Neuroinflammation at
-
Mitochondrial Abnormalities at
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
GBA1, Gba1 | GBA1: Transgenic; Gba1: Knock-Out | Parkinson's Disease | Older transgenic mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system glucosylsphingosine, but not in glucosylceramide, were noted. |
No obvious features noted. |
LRRK2 R1441C KI Mouse
Observed
-
Non-Motor Impairment at 30
Acoustic startle reflex equal to wild-type mice at 12 months of age. Intracellular protein transport impaired in primary cultured cells. PKA activity is elevated in the striatum. Ciliation in striatal cholinergic neurons is decreased at 7 months of age and primary cilia formation is perturbed in the somatosensory cortex.
Absent
-
Dopamine Deficiency at
Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months of age. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice.
-
α-synuclein Inclusions at
No abnormal accumulation of α-synuclein observed at 3, 12, and 22 months of age in the substantia nigra pars compacta or locus coeruleus.
-
Neuroinflammation at
GFAP immunoreactivity was normal at 12 and 22 months of age. However, upon α-synuclein fibril injection, KI mice exhibited increased infiltration of pro-inflammatory monocytes into the brain.
-
Motor Impairment at
Spontaneous locomotor activity (open-field test) equal to wild-type mice at 3, 12, and 24 months of age. Involuntary motor movement (Rotarod) equal to wild-type mice 3 and 12 months of age.
-
Neuronal Loss at
No loss of dopaminergic (TH-immunoreactive) neurons in the substantia nigra pars compacta at 12 and 22 months of age. No loss of TH-immunoreactive neurons in the locus coeruleus.
No Data
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2: Knock-In | Parkinson's Disease | No loss of dopaminergic (TH+) neurons in the substantia nigra pars compacta at 12 and 22 months. No loss of TH-immunoreactive neurons in the locus coeruleus. Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice. |
Acoustic startle reflex equal to wild-type mice at 12 months of age. Motor learning impaired upon antagonism of dopamine receptors (D1 and D2). |
LRRK2 G2019S KI Mouse
Observed
-
Non-Motor Impairment at 16
Altered responses to social-defeat stress (males, 3-4 mos) which correlated with changes in striatal plasticity and intrinsic membrane excitability. Attention deficits, slower information processing, impaired goal-directed learning in 2-6-month-old male KI mice, but cognitive flexibility and novel objective recognition are intact (2-6 mos). Perturbed sleep behavior at 8-10 mos.
-
Motor Impairment at 81
A battery of motor tests revealed no baseline deficits at 3-4, 12-13, and 18-19 months of age. However, an increased locomotor response after amphetamine challenge is observed at 18 months. Motor defects are exacerbated following a manganese stressor.
Absent
-
Dopamine Deficiency at
Striatal dopamine levels do not differ at 2 months of age, and neither do tyrosine hydroxylase levels in the substantia nigra.
-
Neuronal Loss at
The cytoarchitecture of the neocortex, striatum, hippocampus, and elsewhere is normal in Nissl-stained brain sections of 3-4 month-old mice, and striatal levels of tyrosine hydroxylase are similar to those of controls at P21. In another study, tyrosine hydroxylase levels are reduced in the striatum and midbrain at 2 months of age.
No Data
-
α-synuclein Inclusions at
No data.
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2: Knock-In | Parkinson's Disease | Levels of phospho-substrates of LRRK2 (e.g., Rab10) are increased in the brain. Endocytosis and axonal transport defects in neurons. Cholinergic innervation density is lower in the prelimbic/infralimbic cortical areas and dorsomedial striatum, but not in the dorsal lateral geniculate nucleus in 2-6-month-old males. Microglial immunostaining is similar in the striatum and midbrain at 8 weeks |
Attention deficits, slower information processing speeds, and impaired goal-directed learning are evident in 2-6-month-old mice—deficits rescued by systemic administration of the acetylcholinesterase inhibitor donepezil. Cognitive flexibility and novel objective recognition similar to controls. Sleep behavior is perturbed at 8-10 months of age. |
LRRK2 G2019S Mouse (BAC Tg)
Observed
-
Dopamine Deficiency at 52
Age-related decline in striatal dopamine content. Levels were decreased at 12 months of age, but not significantly different from controls at 6 months of age. Also, decreased dopamine metabolite homovanillic acid (HVA).
-
Non-Motor Impairment at 26
Tg mice spend less time in the REM sleep phase at 12 and 18 months of age. Age-dependent increase in plasma corticosterone (present starting at 6-8 months of age). Nuclear envelope integrity is perturbed in dopaminergic neurons at 12 months.
-
Neuroinflammation at 8
Application of α-synuclein fibrils leads to exacerbated responses (more inclusions and greater infiltration of pro-inflammatory monocytes).
-
Motor Impairment at 78
Behavior in hemizygous mice was comparable to littermate controls in terms of activity levels (open-field test) and coordination (beam-walk test) at 6 and 12 months, , but not at 18 months of age, when Tg mice develop motor deficits (Rotarod).
-
Mitochondrial Abnormalities at 0
Primary cultured cells from Tg mice exhibit mitochondrial fragmentation and membrane depolarization.
Absent
-
α-synuclein Inclusions at
No evidence of α-synuclein inclusions up to 18 months of age. However, there is mixed evidence on whether cultured mutant hippocampal neurons have increased levels of α-synuclein protein. After exposure to exogenous α-synuclein fibrils, mutant neurons developed more α-synuclein inclusions than non-Tg neurons.
-
Neuronal Loss at
No evidence of neuronal or other cell death in any brain region, including the cortex, striatum, and hippocampus. There was no difference in the number of dopaminergic neurons in the substantia nigra compared to littermate controls at 6 or 12 months.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2 G2019S | LRRK2: Transgenic | Parkinson's Disease | Brain appears normal. No neuronal or cell death at 12 months. Impaired neurite motility and synaptic vesicle endocytosis in cultured neurons. No increase in α-synuclein or ubiquitin levels or aggregation; however, cultured neurons developed more inclusions when exposed to exogenous α-synuclein fibrils. Decreased striatal dopamine content, decreased evoked release. |
Apparently normal behavior. No change in activity level or motor coordination at 12 months. Motor deficits appear at 18 months. |
LRRK2 G2019S Mouse (Tg)
Observed
-
Non-Motor Impairment at 45
Anxiety/depression-like symptoms were observed at 10-12 months of age.
-
α-synuclein Inclusions at 52
Around 2 years of age, mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex. However, one study found α-synuclein accumulation in whole brain lysates of 12- to 19-month-old transgenic mice.
-
Neuroinflammation at 63
Around 2 years of age, mice did not have GFAP abnormalities in the ventral midbrain, striatum, or cerebral cortex. However, activated microglia were reported in the striatum at 14 months, and CD68 and TNF-α levels were increased in whole brains at 4-6 months. Others have not observed differences in Iba-1 staining (microglial marker) at 6, 12, or 18 months in the striatum or substantia nigra.
-
Motor Impairment at 35
Rotarod performance deteriorated in 14- to 18-month-old mice, but minor deficits are already observed as early as 8 months of age. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex.
-
Mitochondrial Abnormalities at 63
Increased numbers and condensation of mitochondria in striatal microglia were reported at 14 months. Abnormally high levels of condensed mitochondria were also observed in cortical and striatal neurons at 17-18 months.
-
Neuronal Loss at 83
By 19-21 months, mice lose 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta and 14 percent of dopaminergic dendrites in the substantia nigra pars reticulata. At 1-2 months neuronal numbers were normal. Some authors do not see differences in TH staining up to 2 years of age. No abnormal neuronal loss is observed in the ventral tegmental area or cerebellum.
Absent
-
Dopamine Deficiency at
At 14-15 months of age, hemizygous mice had normal levels of striatal dopamine, DOPAC, and HVA. However, in the olfactory bulb, levels of HVA and DOPAC were lower, but dopamine was unchanged.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2 G2019S | LRRK2: Transgenic | Parkinson's Disease | Age-dependent dopaminergic neuron degeneration in the substantia nigra, though reports are mixed. No reduction in striatal dopaminergic terminals or dopamine levels. Some reports of α-synuclein accumulation. Abnormal mitochondria in striatal neurons and microglia; accumulation of autophagic vacuoles. Evidence for activated striatal microglia and increased levels of CD68 and TNF-α in whole brain. |
Deterioration of Rotarod performance in 14- to 18-month-old mice. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex. Anxiety/depression-like symptoms at 10-12 months. |
LRRK2 G2019S Rat (BAC Tg)
Observed
-
Non-Motor Impairment at 26
Bone marrow myeloid progenitor numbers were decreased, but suppressive myeloid cells were increased at 6 to 11 months of age
-
Motor Impairment at 35
Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages.
Absent
-
Dopamine Deficiency at
No change in striatal dopamine levels. No change in 3,4-dihydroxyphenylacetic acid (DOPAC) levels. No change in the rate of dopamine turnover. At 12 months of age Tg rats exhibited higher levels of striatal homovanillic acid (HVA).
-
α-synuclein Inclusions at
Under basal conditions no α-synuclein inclusions were observed.
-
Neuroinflammation at
No increase in Iba-1 positive microglia or GFAP-positive astrocytes in the substantia nigra at 12 months of age. However, iNOS expression was elevated in nigral dopaminergic neurons.
-
Neuronal Loss at
No overt loss of dopaminergic neurons in the substantia nigra out to 12 months of age.
No Data
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2 G2019S | LRRK2: Transgenic | Parkinson's Disease | No overt neurodegeneration out to 12 months of age. Elongated dopaminergic neurons. Elevated oxidative and nitrosative stress. No evidence of gliosis. No α-synuclein inclusions until challenged with exogenous α-synuclein. No change in dopamine levels. |
Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages. |
Lrrk2 KO Mouse
Observed
-
Neuroinflammation at 87
Striatal staining of GFAP, a marker of reactive astrocytosis, did not differ between control and KO mice, but cells positive for Iba1 staining, a marker of activated microglia, were moderately enlarged in the striatum of 20 -month-old KO mice. Cx3cr1 mRNA levels higher in KO mouse brains.
-
Motor Impairment at 52
Motor behavior is generally intact up to 18 months based on Rotarod and open field tests. However, some age-dependent effects are observed on the open field test: 12 -month-old mice traveled longer distances and had higher walking speeds versus controls, which was not apparent in 3- or 24-month-old mice. Older (24 months) mice had deficits in motor skill learning as measured by Rotarod.
-
Mitochondrial Abnormalities at 9
Adult (9 - to 23-week-old) Lrrk2 KO mice exhibit enhanced mitophagy in dopaminergic neurons of the substantia nigra pars compacta, as detected by an increase in the number of mitolysosomes.
Absent
-
Dopamine Deficiency at
Levels of TH in the striatum are equal between genotypes in 18- to 24-month-old mice.
-
Non-Motor Impairment at
No differences were observed between KO and wild-type mice across 6 to 24 months of age on several behavioral tests, including the elevated plus maze for anxiety-like behavior, the buried treat test to measure hyposmia, the grip strength test for forelimb strength, or working memory as measured by spontaneous alternation.
-
α-synuclein Inclusions at
No abnormal accumulation of α-synuclein in the cell bodies of striatal neurons observed in 20-month-old KO mice.
-
Neuronal Loss at
Neuronal Loss No differences between KO and wild-type mice up to 24 months of age in the number of tyrosine hydroxylase (TH)–positive cells in the substantia nigra pars compacta. No neurodegeneration markers observed in the striatum and cortex at 20 months. Cerebral cortex and dorsal (but not ventral) striatum volumes reduced at 12 months.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Lrrk2 | Lrrk2: Knock-Out | Parkinson's Disease | No loss in the number of TH–positive cells in the substantia nigra pars compacta up to 24 months. Cerebral cortex and dorsal striatum volumes reduced at 12 months. Striatal spiny projection neurons were enlarged and the frequency of nuclear invaginations was increased at 12 months, suggesting premature aging. Dendritic morphology perturbed at 12 months. |
No differences between KO and wild-type mice up to 24 months on several behavioral tests, including the elevated plus maze for anxiety-like behavior, the buried treat test to measure hyposmia, the grip strength test for forelimb strength, or working memory as measured by spontaneous alternation. Older (24-month-old) mice showed deficits in motor skill learning as measured by Rotarod. |
Lrrk2 KO Rat
Observed
-
Non-Motor Impairment at 5
Abnormalities occur in peripheral organs, most notably the kidney, but also the liver, lung, and spleen. Changes are progressive, although they do not appear to shorten lifespan. The earliest reported alterations occur in the kidneys at 1 month of age.
Absent
-
Dopamine Deficiency at
Basal levels of dopamine metabolites (3,4-dihydroxyphenylacetic and homovanillic acid) do not differ between Lrrk2 KO and wild-type rats at 4, 8, and 12 months of age. Evoked release of dopamine also does not differ between KO and wild-type rats.
-
Neuroinflammation at
When challenged with LPS or α-synuclein overexpression, Lrrk2 KO rats show lower levels of pro-inflammatory CD68-positive myeloid cells in the substantia nigra than wild-type rats.
-
Motor Impairment at
Assessment of Rotarod performance revealed no impairment at 12 months of age compared with wild-type rats.
-
Neuronal Loss at
Under basal conditions, the number of TH-positive cells in the substantia nigra is comparable between Lrrk2 KO and wild-type rats. When challenged with LPS or α-synuclein overexpression, Lrrk2 KO rats develop significantly less neurodegeneration in the substantia nigra than wild-type rats.
No Data
-
α-synuclein Inclusions at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Lrrk2 | Lrrk2: Knock-Out | Parkinson's Disease | Not observed. Protection against dopaminergic cell loss under conditions involving LPS or α-synuclein overexpression in the substantia nigra. No changes in basal or evoked release of dopamine. |
One assessment of Rotarod performance revealed no impairment at 12 months of age compared with wild-type rats. |
LRRK2 R1441C Mouse (Tg - Conditional)
Observed
Absent
-
Dopamine Deficiency at
HPLC analysis of striata from 10-month-old mice revealed no significant differences in the levels of dopamine or its metabolites DOPAC and HVA.
-
Non-Motor Impairment at
Olfactory function, as assessed by the ability to locate buried food, was normal out to 20 months of age.
-
α-synuclein Inclusions at
Immunohistochemical analysis of the brain at 22 months did not reveal abnormalities in α-synuclein, and no proteinaceous inclusions were seen.
-
Neuroinflammation at
Immunohistochemical analysis of the brain at 22 months found GFAP and Iba1 immunoreactivity comparable to control levels.
-
Motor Impairment at
Around 20 months of age, R26-LRRK2 mice behaved normally, exhibiting no deficits in locomotor activity (open-field test), motor coordination (Rotarod), or gait (digital CatWalk system).
-
Neuronal Loss at
In the substantia nigra pars compacta, there was no difference in the number of TH-positive neurons or the total number of Nissl-positive neurons at 12 and 22 months.
No Data
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2 R1441C | LRRK2: Transgenic | Parkinson's Disease | No neurodegeneration in the brain. No proteinaceous inclusions of α-synuclein, ubiquitin, or tau. No reactive gliosis. No change in dopamine levels. Subtle morphological abnormalities in dopaminergic and non-dopaminergic neuronal nuclei, including altered nuclear envelope. |
No overt behavioral differences. Activity levels and Rotarod performance are normal into advanced age. |
LRRK2 WT Mouse (BAC Tg)
Observed
-
Dopamine Deficiency at 52
Striatal dopamine levels, as measured by PET imaging with [18F]FDOPA uptake, are higher in WT-OX versus non-Tg mice.
-
Motor Impairment at 52
WT-OX mice (12 months) are hyperactive on several parameters of the open-field test. Gait analysis (Cat-Walk system) was also perturbed relative to non-Tg controls. However, the number of rears did not differ.
Absent
-
Mitochondrial Abnormalities at
Mitochondrial morphology and levels of proteins involved in mitochondrial fission (Drp1 and Fis1) are normal at 12 months of age.
No Data
-
Non-Motor Impairment at
No data.
-
α-synuclein Inclusions at
No in vivo data, but α-syn colocalization with LAMP-2 is increased in cultured neurons from WT-OX mice.
-
Neuroinflammation at
No data.
-
Neuronal Loss at
No data on neuron numbers are available, but neurite length is reduced in primary hippocampal neurons and primary nigral tyrosine hydroxylase-positive neurons of WT-OX mice versus non-Tg mice.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2: Transgenic | Parkinson's Disease | Overtly normal brain structure. Intact, but shorter, neurites. |
Motor hyperactivity at 12 months of age. |
Parkin KO Rat
Observed
-
Non-Motor Impairment at 9
Orientation to an olfactory stimulus was normal. At 2 months of age, male KO rats had a greater preference for methamphetamine than wild-type rats based on self-administration and place preference tests.
-
Mitochondrial Abnormalities at 14
Alterations in mitochondrial protein expression in synaptic and nonsynaptic striatal samples of 3-month-old KO rats.
-
Neuronal Loss at 35
A small, non-significant reduction in dopaminergic neurons was observed in the substantia nigra at 8 months of age.
Absent
-
Dopamine Deficiency at
No differences in striatal dopamine levels at 4, 6, or 8 months. Altered dopaminergic transmission factors in the striata, including MAO, β-phenylethylamine, trace amine-associated receptor 1, and postsynaptic dopamine D2 receptors in 2-month-old KO rats. Striatal dopamine metabolite levels decreased with age in KO rats, showing lower levels at 12 months than at 8 months.
-
α-synuclein Inclusions at
There was no increase in α-synuclein protein in the striatum or any other brain region assessed.
-
Motor Impairment at
No behavioral deficits were detected at 4, 6, and 8 months of age. Motor functioning, including performance on the Rotarod, was intact. However, at 2 months, male KO rats made fewer small stereotypic movements, such as scratching and grooming, than wild-type controls.
No Data
-
Neuroinflammation at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Park2 | Park2: Knock-Out | Parkinson's Disease | No significant changes in dopaminergic neurons in the substantia nigra nor striatal dopamine levels, but alterations in dopaminergic signaling were detected at an early age, as were disruptions in mitochondrial protein expression in striatum. No increase in α-synuclein. Evoked release of striatal glycine greater at 12 months versus wild-type rats. |
No behavioral deficits detected at 4, 6, and 8 months of age. However, at 2 months, male KO rats made fewer small stereotypic movements, such as scratching and grooming, than wild-type controls. At 2 months, male KO rats had a greater preference for methamphetamine than wild-type rats. |
Parkin Q311X Mouse (BAC Tg)
Observed
-
Dopamine Deficiency at 69
Surviving nigral neurons at 16 months of age had reduced tyrosine hydroxylase expression. By 19-21 months, striatal concentrations of dopamine and the dopamine metabolite DOPAC were decreased compared with non-Tg littermates.
-
Non-Motor Impairment at 68
Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.
-
Non-Motor Impairment at 71
Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.
-
α-synuclein Inclusions at 72
Lewy body-like inclusions were not observed at any age, however, mutant mice exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in the substantia nigra at 16 months of age.
-
Motor Impairment at 70
Behavior was fairly normal at 3 months, but motor abnormalities were detected by 16 months of age, including hypoactivity and deficits in coordination and in motor response to sensory stimuli.
-
Mitochondrial Abnormalities at 4
Mitochondrial dysfunction observed as early as 1 month of age, based on electron microscopy (e.g., lacking an outer membrane, swollen) and expression of the short isoform of OPA1.
-
Neuronal Loss at 26
Progressive loss of dopaminergic neurons in the substantia nigra, starting as early as 6 months of age. About 40 percent loss by 16 months of age with a corresponding decrease in dopaminergic projections to the striatum. Neurons in the ventral tegmental area were relatively spared.
Absent
No Data
-
Neuroinflammation at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Park2 | Parkin Q311X | Park2: Transgenic | Parkinson's Disease | Degeneration of dopaminergic neurons in the SN and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein damage. Dysfunction in the burst-firing pattern activity of dopaminergic SN neurons and increased expression of markers for excitotoxic damage. |
Late-onset hypoactivity (about 16 months of age), other modest changes in motor behavior and coordination in tests that included traversing a beam or removing adhesive. |
Parkin S65A KI Mouse
Observed
-
Motor Impairment at 53
Impaired performance on the raised balance beam at 12 and 18 months of age in homozygous KI mice. No deficits in Rotarod performance or gait analysis.
-
Mitochondrial Abnormalities at 52
Mitochondrial respiration (respiratory control ratio) was impaired in an age-dependent manner—at 12 months, but not at 3 months—in homozygous KI mice. No deficits in basal mitophagy.
Absent
-
Dopamine Deficiency at
No differences in levels of striatal dopamine and 3,4-DOPAC, nor in their ratio, between 18-month-old homozygous KI mice and wild-type mice.
-
Neuroinflammation at
Immunolabeling of astrocytes (GFAP) and microglia (Iba1) did not differ between homozygous Parkin KI mice and wild-type mice.
-
Neuronal Loss at
No deficits in striatal anatomy or volume or in nigrostriatal innervation in 18-month-old homozygous KI mice.
No Data
-
Non-Motor Impairment at
No data.
-
α-synuclein Inclusions at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Park2 | Park2 S65A | Park2: Knock-In | Parkinson's Disease | No evidence of nigrostriatal neuropathology in 18-month-old homozygous mice. |
Motor dysfunction on the raised balance beam by 12 months of age. No deficits in Rotarod performance or gait. |
PINK1 G309D (PINK1-/-) Mouse (KI)
Observed
-
Dopamine Deficiency at 39
Decreased dopamine concentration in the striatum by 9 months of age.
-
Neuroinflammation at 81
Expression of factors involved in Toll-like receptor signaling were increased in the cerebellum, as were astrocytic and microglial markers in the corticospinal tract and striatum at 18 months.
-
Motor Impairment at 70
At 16 months of age Pink1-/- mice exhibited decreased spontaneous locomotor activity. Strength and coordination were intact.
-
Mitochondrial Abnormalities at 13
By 3 months of age the mice exhibited a mitochondrial import defect. This phenotype was more severe at 6 months and import was reduced nearly 50% by 12 months of age. By 6 months, ATP production, respiration, and mitochondrial membrane potential were also reduced.
Absent
-
Non-Motor Impairment at
Mutant mice performed similarly to wild-type mice in tests assessing the startle reflex, sweating, and anxiety.
-
α-synuclein Inclusions at
No Lewy body-like inclusions or α-synuclein aggregates in the brainstem or substantia nigra, but expression levels of α-synuclein are altered in brainstem/midbrain.
-
Neuronal Loss at
Neuronal loss was not observed at 18 months of age (total neuronal population and TH-positive subset).
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
PINK1 | Pink1 G309D | PINK1: Knock-In | Parkinson's Disease | No neuronal loss. No Lewy bodies or α-synuclein aggregates, but α-synuclein expression change in brainstem/midbrain. Low dopamine levels. Mitochondrial dysfunction (e.g., reduced ATP, reduced respiratory activity). Increase in factors involved in Toll-like receptor signaling in the cerebellum, and increased astrocytic and microglial markers in the corticospinal tract and striatum. |
Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination. |
PINK1 KO Mouse
Observed
-
Non-Motor Impairment at 0
Modest vocalization deficits observed at 4-6 months. Reduced BDNF levels in the midbrain and cortex at 10 months. Cardiac hypertrophy observed at 2 and 6 months of age.
-
Motor Impairment at 23
Reduced spontaneous locomotor activity and skill reported at 3-6 months.
-
Mitochondrial Abnormalities at 9
Altered shape, density, and movement of dendritic mitochondria observed in cultured primary neurons from embryonic mice. Also, an abnormal rise in serum cytokines in response to acute mitochondrial stress was reported in vivo. By 2 months of age, mitochondrial dysfunction observed in cardiomyocytes.
Absent
-
Dopamine Deficiency at
Overall striatal levels of dopamine did not significantly differ from levels in wild-type mice at 2-3 months or 8-9 months of age.
-
Neuronal Loss at
No decrease in the number of dopaminergic neurons in the substantia nigra at 2-3 months or 8-9 months of age. Neuronal morphology also grossly intact.
No Data
-
α-synuclein Inclusions at
No data.
-
Neuroinflammation at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Pink1 | Pink1: Knock-Out | Parkinson's Disease | Normal numbers of dopaminergic neurons and tyrosine hydroxylase levels in substantia nigra at 8-9 months of age. Alterations in the dendrites of midbrain dopaminergic neurons and cultured cortical neurons. Altered shape, density, and movement of dendritic mitochondria in cultured primary neurons from embryonic mice. Reduced BDNF levels in the midbrain and cortex at 10 months. |
Reduced spontaneous locomotor activity and skill at 3-6 months. Modest vocalization deficits at 4-6 months. |
Pink1 KO Rat
Observed
-
Non-Motor Impairment at 9
Nociception alterations in male KO rats observed at 6 to 10 months of age, indicating thermal hyperalgesia. This effect was present in female KO rats at 2 months of age, but not at older ages. Abnormalities in ventilation frequency were also observed in male KO rats. Defects in ultrasonic vocalizations starting at 2 months of age in male and female KO rats.
-
α-synuclein Inclusions at 18
Alpha-synuclein aggregates were found as early as 4 months of age and increased in number up to 12 months. Areas affected include the periaqueductal gray, substantia nigra pars compacta, locus coeruleus, nucleus ambiguous, cortex, thalamus, and striatum.
-
Motor Impairment at 5
Abnormalities in gait, coordination, and strength. By 5 weeks, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor behaviors. Deficits in gait may be transient. Partial reversal of motor impairment by Levodopa.
-
Mitochondrial Abnormalities at 18
Alterations in mitochondrial metabolites and mitochondrial protein expression were reported as early as 4 months of age in cortex and striatum. Oxygen consumption rates were elevated in striatal mitochondria isolated from 9-month-old rats, but not in non-synaptic samples from 3-month-old rats.
-
Neuronal Loss at 11
Age-related decrease in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra. A reduction of 25 and 50 percent at 6 months and 8 months, respectively. Deficits in TH staining in the substantia nigra have been observed as early as at 2.5 months of age. While some studies did not see any changes in TH-positive cells in the striatum, others have observed a 15% loss.
Absent
-
Dopamine Deficiency at
One study found striatal dopamine levels were increased two- to threefold in Pink1 KO rats compared with wild-type levels at 8 months of age, whereas another reported a slight decrease at this age. In the dorsal striatum, KO rats have age-dependent differences in basal and evoked dopamine levels, but no differences were observed compared to wild-type rats.
No Data
-
Neuroinflammation at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Pink1 | Pink1: Knock-Out | Parkinson's Disease | Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Alterations in striatal dopamine and serotonin levels. Progressive increase in α-synuclein aggregates and reduced brain volume across numerous regions. Increased ventricular volume. Alterations in cortical and striatal mitochondria. |
Abnormalities in gait, coordination, and strength. As early as 5 weeks of age, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor (lingual) behaviors. |
Thy1-αSyn “Line 61” Mouse
Observed
-
Dopamine Deficiency at 63
Line 61 mice lose striatal dopamine progressively, starting at about 14 months of age. Between approximately 6 and 10 months, however, the neurotransmitter’s extracellular levels are transiently increased.
-
Non-Motor Impairment at 11
Disruptions in olfaction, circadian rhythms, sleep, cognition, social behavior, and autonomic function have been reported. Several are reminiscent of PD non-motor impairments. Alterations in olfaction, circadian rhythms, and the autonomic regulation of heartrate occur as early as 3 months of age.
-
α-synuclein Inclusions at 4
Proteinase K-resistant aggregates are seen at 1 month and increase with age, including the substantia nigra, periqueductal gray, cortex, striatum, vagus, olfactory bulb, thalamus, locus coeruleus, and cerebellum, as well as cholinergic neurons in the colon. Elevated levels of phospho-serine 129 α-synuclein are found in the substantia nigra, striatum, cortex, frontal cortex, and hippocampus.
-
Neuroinflammation at 5
Neuroinflammation markers have been seen in the cortex, striatum, substantia nigra, and hippocampus. The time course and profile vary between brain regions and some features remain subject to debate. However, neuroinflammation appears to affect the striatum first (1 month), and then the substantia nigra (5–6 months). At older ages, particularly in the substantia nigra, inflammation attenuates.
-
Motor Impairment at 4
Impairments in balance, coordination, muscle strength, fine motor skills, vocalizations, and stress-induced defecation arise between 1 and 3 months. Transient hyperactivity is seen between 4 and 9 months of age, followed by hypoactivity and sensorimotor deficits at about 15 months. As the phenotype becomes more severe, the mice develop difficulty eating, akinesia, and hunched posture.
-
Mitochondrial Abnormalities at 18
The functions of mitochondrial respiratory complexes in midbrain and striatum are impaired, with the earliest reported deficit affecting complex I in the midbrain at 4 months. Elevated α-synuclein accumulation was found in mitochondria of the midbrain, striatum, and cortex.
-
Neuronal Loss at 16
Although neuron loss occurs in the neocortex and hippocampal CA3 region as early as 3–4 months of age, there is no reduction in the PD-relevant dopaminergic neurons of the substantia nigra, even at 22 months of age.
Absent
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SNCA | SNCA: Transgenic | Parkinson's Disease |
Vps35 p.D620N KI Mouse
Observed
-
Dopamine Deficiency at 13
Enhanced peak amplitude in dopamine release and prolonged reuptake kinetics in acute striatal slices from 3-month-old mice; decreased DAT and increased VMAT2. Basal levels of dopamine and metabolites in dorsolateral striatum did not differ, but the DOPAC+HVA/DA ratio was increased. At 16 months, dopamine in striatal homogenates was reduced, but levels of metabolites (DOPAC, HVA) did not differ.
-
α-synuclein Inclusions at 65
No differences in α-synuclein puncta density or distribution in the SNpc at 3 months. No pathological α-synuclein observations seen throughout the brain at 13 months. However, at 15 to 16 months, increased somatic α-synuclein immunoreactivity found in the SNpc, and increased α-synuclein oligomers and aggregated α-synuclein observed in the ventral midbrain.
-
Neuroinflammation at 64
Increased GFAP immunostaining in the SNpc, but not in the striatum, of 15- to 16-month-old VKI mice; no GFAP differences observed at earlier ages. No differences in microgliosis (Iba-1 immunostaining) in the SNpc or the striatum up to 16 months of age.
-
Motor Impairment at 60
Motor deficiencies on the open-field test and the beam walking test appear at 14 months of age, but not earlier from 3 to even 13 months of age. However, performance on other motor tests—Rotarod and grip strength—did not differ at the advanced age (14 months). No deficits seen in the cylinder test (rearing) at 3 months. Amphetamine-induced hyperlocomotion is rescued by LRRK2 kinase inhibition.
-
Mitochondrial Abnormalities at 61
Mitochondrial structure, assesed by EM, was perturbed at 14 months, but not at 3 months, of age. Mitochondrial function—namely, the oxygen consumption rate—was reduced in older (15-month-old) mice.
-
Neuronal Loss at 56
Loss of TH-positive neurons in the SNpc and loss of TH-positive nerve terminals in the striatum at 13-16 months. Widespread axonal degeneration in the brain at 13 months.
Absent
-
Non-Motor Impairment at
No deficits in the buried pellet test, measuring olfactory function, from 6 to 14 months of age. No defects in gastrointestinal function (as measured by stool frequency and water content) up to 14 months of age.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Vps35 | Vps35: Knock-In | Parkinson's Disease | Loss of TH+ neurons in SNpc and TH+ terminals in striatum at 13-16 mos. Widespread axonal degeneration at 13 mos. Increased somatic α-synuclein in SNpc; α-synuclein oligomers and aggregates in ventral midbrain at 15-16 mos. Increased somatodendritic tau/p-tau with age, but no neurofibrillary pathology. Increased GFAP in SNpc, but not striatum at 15-16 mos. No microgliosis up to 16 mos. |
No deficits in the buried pellet test, measuring olfactory function, from 6-14 months. Deficits in mood (anxiety/apathy) and/or cognition on elevated plus maze, starting at 3 months (unpublished). |
α-synuclein A30P/A53T Mouse (Tg)
Observed
-
Dopamine Deficiency at 9
Striatal dopamine concentrations were lower at all ages tested, including the earliest age, 2-3 months. Dopamine concentrations dropped with age, and levels of metabolites (e.g., DOPAC and HVA) were also lower in HM2 mice than non-Tg by 13-23 months of age.
-
Motor Impairment at 30
At young age 2-3 months, HM2 mice were more active than non-Tg controls, but by middle age (7-9 months) they were less active. At advanced ages (13-23 months), they also exhibited impaired coordination as measured by the time it took to right themselves from an inverted wire screen. However, no deficiencies in Rotarod performance, grip strength, or open-field movements were detected at 6 months.
-
Neuronal Loss at 34
Progressive loss of dopaminergic neurons was reported in the substantia nigra pars compacta (19 percent reduction at 8.5 months and 55 percent at 19 months).
Absent
-
α-synuclein Inclusions at
Inclusions were not observed at any age. Diffuse α- synuclein protein was both cytoplasmic and nuclear.
No Data
-
Non-Motor Impairment at
No data.
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SNCA | SNCA A30P, SNCA A53T | SNCA: Transgenic | Parkinson's Disease | Progressively loss of dopaminergic neurons in the substantia nigra pars compacta, observed by 8.5 months. No α-synuclein inclusions. Morphological abnormalities in the dopaminergic system, including axonal and dendritic abnormalities, reduced dopamine concentration in the striatum. |
More active as young adults, then hypoactive compared to non-Tg. Also reduced motor coordination in old age as measured by the time to right from an inverted wire screen. |
α-synuclein A53T Mouse (Tg)
Observed
-
Dopamine Deficiency at 23
In symptomatic mice, striatal dopamine and metabolites DOPAC and HVA are comparable to wildtype, but at 5 months, striatal tyrosine hydroxylase is reduced. Increased D1 receptors in the substantia nigra and decreased dopamine transporters in the nucleus accumbens and striatum have been reported.
-
Non-Motor Impairment at 50
At 11–12 months, spatial memory was impaired as assessed by the Barnes circular maze.
-
α-synuclein Inclusions at 35
Prior to motor deficits, these mice develop accumulations of α-synuclein in select neuronal populations, including the midbrain, cerebellum, brainstem, and spinal cord. The protein aggregates do not resemble Lewy bodies, but are thioflavin-S-positive, indicating fibrillar structure.
-
Neuroinflammation at 40
In symptomatic mice, increased GFAP immunoreactivity was observed in select brain regions, including the dorsal midbrain, deep cerebellar nuclei, brainstem, and spinal cord. Cortex, hippocampus, and substantia nigra did not have increased reactivity compared with non-Tg controls.
-
Motor Impairment at 32
These mice develop severe motor impairment starting around 9-16 months of age. The deficits start out with mild hyperactivity at 7 months and progress to a wobbling movement, decreased activity, and ultimately paralysis and death.
-
Mitochondrial Abnormalities at 56
At 11–14 months, mitochondria in brainstem neurons were enlarged and their co-localization with the mitochondrial fission protein Drp1 was reduced.
Absent
-
Neuronal Loss at
Overt neuronal loss was not reported in these mice.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SNCA | SNCA A53T | SNCA: Transgenic | Parkinson's Disease | No overt neuronal loss. Alterations in dopaminergic-associated proteins in the striatum, substantia nigra, and nucleus accumbens. Region-specific neuronal accumulation of fibrillar α-synuclein, ubiquitin, and neurofilament-H, and accompanying astrocytosis. |
Early hyperactivity followed by severe motor impairment, manifesting as wobbling, posturing, decreased spontaneous locomotor behavior, inability to navigate the Rotarod, and ultimately paralysis and death. At 11–12 months, spatial memory impaired as assessed by the Barnes circular maze. |
α-synuclein A53T Mouse (Tg) on SNCA KO
Observed
-
Non-Motor Impairment at 14
By 3 months of age, the mice develop gastrointestinal dysfunction.
-
Motor Impairment at 26
By 6 months of age, homozygous mice became hypoactive, traveling less distance. This was not attributed to changes in exploratory behavior caused by anxiety. Also at 6 months, differences in performance on the accelerating Rotarod were seen.
Absent
-
Dopamine Deficiency at
No differences in striatal dopamine concentrations, or dopaminergic metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) at 11 and 18 months of age.
-
α-synuclein Inclusions at
No evidence of Lewy body-like inclusions in the brain at any age. Likewise α-synuclein aggregates were not observed in the brain, although they did occur in enteric neurons in the gut.
-
Neuronal Loss at
No evidence of neuronal cell loss in the substantia nigra at 11 and 18 months of age, including dopaminergic neurons (TH-positive neurons) and total neurons.
No Data
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SNCA | SNCA A53T | SNCA: Transgenic; SNCA: Knock-Out | Parkinson's Disease | No loss of dopaminergic neurons in the substantia nigra by 18 months of age. Rare dystrophic synapses in the hippocampus at advanced age, but no Lewy body-like pathology or α-synuclein aggregation in the brain. No change in striatal dopamine concentration. |
Impaired performance on the Rotarod and reduced spontaneous locomotor activity in open-field test. |
α-synuclein E46K Rat (BAC Tg)
Observed
-
α-synuclein Inclusions at 52
By 12 months of age, intracellular aggregates were observed in dopaminergic neurons of the substantia nigra and ventral tegmental area. Aggregates noted to be fairly small compared to those observed in PD brain. In the striatum and cortex α -synuclein accumulation appeared primarily in neuronal processes.
Absent
-
Dopamine Deficiency at
No dopamine deficiency in the striatum at 12 months of age. No serotonin deficiency in the striatum. Dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid were reduced by approximately 25 percent and transmitter turnover was decreased.
-
Motor Impairment at
No overt motor differences out to 12 months of age, unless challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.
-
Neuronal Loss at
No overt loss of dopaminergic neurons out to 12 months of age.
No Data
-
Non-Motor Impairment at
No data.
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SNCA | SNCA E46K | SNCA: Transgenic | Parkinson's Disease | No overt neuronal loss. Accumulation of mutant α-synuclein in the brain, in the form of diffuse staining and intracellular aggregates. Aggregates were largely restricted to dopaminergic neurons of the substantia nigra and ventral tegmental area. Elevated nitrotyrosine in dopaminergic neurons. |
No overt behavioral changes until challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity. |
α-synuclein KO Mouse
Observed
-
Neuroinflammation at 16
Microglia cultured from Snca KO brain were more reactive, ramified. They had vacuole-like structures. Snca KO microglia exhibited exacerbated response to LPS, with greater secretion of pro-inflammatory cytokines.
-
Motor Impairment at 26
Motor function was largely intact. Normal performance on the Rotarod and in total distance travelled in the open field test. Subtle differences only (e.g., less rearing behavior than controls). They also spent less time in the center of the field, suggesting a possible anxiety-related phenotype.
-
Mitochondrial Abnormalities at 39
Mitochondrial abnormalities include reduced levels of the mitochondrial phospholipid cardiolipin and reduced activity of electron transport chain complex I/III.
Absent
-
Non-Motor Impairment at
The mice had normal reflexes and sensory abilities. Also, learning and memory appeared intact at 6-10 months of age, as assesed by the Morris water maze and tests of conditioned fear memory.
No Data
-
Dopamine Deficiency at
A possible modest reduction in striatal dopamine level, but highly variable from mouse to mouse.
-
α-synuclein Inclusions at
No data.
-
Neuronal Loss at
No gross abnormalities in the brain.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SNCA | SNCA: Knock-Out | Parkinson's Disease | No gross brain abnormalities. Electron microscopy revealed synaptic vesicle abnormalities in hippocampal neurons, i.e., fewer vesicles in the reserve pool. |
Behavior is largely normal. Normal performance on the Rotarod. Subtle differences in locomotor activity (e.g., less rearing) but normal overall distance travelled. Learning and memory appear intact. Possible anxiety-like phenotype. |
α-synuclein KO Mouse (Conditional)
Observed
Absent
No Data
-
Dopamine Deficiency at
No data.
-
Non-Motor Impairment at
No data.
-
α-synuclein Inclusions at
No data.
-
Neuroinflammation at
No data.
-
Motor Impairment at
No data.
-
Mitochondrial Abnormalities at
No data.
-
Neuronal Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SNCA | SNCA: Conditional Knock-out | Parkinson's Disease | No data. |
No data. |