Research Models
Parkinson's Disease
PD models come to Alzforum
22 Mar 2017 Selected rodent models of PD (18 of them!) are now included in the database thanks to generous support from MJFF.
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).
20 Models
20 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
-
Motor Impairment at 5
Abnormalities in gait and strength, vocalizations, and tongue movements were observed. Some animals began dragging their hindlimbs as early as 4-6 weeks. 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.
-
Neuronal Loss at 26
Age-related decreases in tyrosine hydroxylase (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 eight months of age.
-
α-synuclein Inclusions at
Staining for α-synuclein revealed no increase in the striatum or in any other brain region assessed.
No Data
-
Non-Motor Impairment at
No data.
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities 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. |
Abnormalities in gait and strength, vocalizations, and tongue movements. Dragging hind limbs in some animals as early as 4-6 weeks. By 4 months, abnormal paw positioning and a shorter stride. In males, impaired licking, longer and more frequent ultrasonic vocalizations, and accelerated decrease in average call intensity with age. |
LRRK2 G2019S KI Mouse
Observed
-
Non-Motor Impairment at 16
Young adult males (3-4 months old) are unusually resilient to a depression-like syndrome resulting from chronic social stress. Alterations in striatal synaptic plasticity correlate with the phenotype.
-
Motor Impairment at 81
A battery of motor tests revealed no baseline deficits at 3-4, 12-13, and 18-19 months. However, an increased locomotor response after amphetamine challenge was observed at 18 months.
Absent
-
Neuronal Loss at
The cytoarchitecture of the neocortex and striatum appeared normal in Nissl-stained brain sections of 3-4 month-old mice, and striatal levels of tyrosine hydroxylase were similar to those of controls.
No Data
-
Dopamine Deficiency at
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 |
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 six months of age. Also, decreased dopamine metabolite homovanillic acid (HVA).
Absent
-
α-synuclein Inclusions at
No evidence of α-synuclein inclusions up to 18 months of age.
-
Motor Impairment at
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.
-
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 six or 12 months.
No Data
-
Non-Motor Impairment at
No data.
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities at
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. No increase in α-synuclein or ubiquitin levels or aggregation. Decreased striatal dopamine content, decreased evoked release. |
Apparently normal behavior. No change in activity level or motor coordination at 12 months. |
LRRK2 G2019S Mouse (Tg)
Observed
-
Non-Motor Impairment at 45
Anxiety/depression-like symptoms were observed at 10-12 months of age.
-
Neuroinflammation at 63
At around 2 years of age, the mice did not exhibit abnormalities in GFAP in the ventral midbrain, striatum, or cerebral cortex, compared with non-transgenic controls. 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.
-
Motor Impairment at 72
Rotarod performance deteriorated in 14- to 18-month-old mice. There was 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 striatal neurons at 17-18 months.
-
Neuronal Loss at 83
By 19-21 months of age, hemizygous mice lose about 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta and about 14 percent in the substantia nigra pars reticulata. At 1-2 months of age neuronal numbers were normal. The ventral tegmental area did not undergo abnormal neuronal loss.
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.
-
α-synuclein Inclusions at
At around 2 years of age, the mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex.
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. No reduction in striatal dopaminergic terminals or dopamine levels. No evidence of abnormal protein accumulation even at advanced ages. Abnormal mitochondria in striatal neurons and microglia, and accumulation of autophagic vacuoles. Activated striatal microglia; CD68 and TNF-α levels increased in whole brain. |
Deterioration of Rotarod performance in 14- to 18-month-old mice. 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
-
Motor Impairment at 35
Mild abnormalities in motor behavior. Slightly more postural instability at eight 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 transgenic rats exhibited higher levels of striatal homovanillic acid (HVA).
-
α-synuclein Inclusions at
Under basal conditions no α-synuclein inclusions were observed. Inclusions could be induced by exogenous α-synuclein (e.g., viral transduction or fibril intracerebral injection). LRRK2 rats were more prone to inclusion formation under these conditions.
-
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
-
Non-Motor Impairment at
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 eight months of age (but not at four and 12 months). Slightly more rearing events at 12 months, but not at younger ages. |
LRRK2 KO Rat
Observed
-
Non-Motor Impairment at 5
Abnormalities 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. Earliest reported alterations occur in the kidneys at one month of age.
Absent
-
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
One assessment of Rotarod performance revealed no impairment at 12 months.
-
Neuronal Loss at
Under basal conditions, the number of TH-positive cells in the substantia nigra was comparable between Lrrk2 KO rats and wild-type rats. When challenged with LPS or α-synuclein overexpression, Lrrk2 KO rats developed significantly less neurodegeneration in the substantia nigra than wild-type rats.
No Data
-
Dopamine Deficiency at
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. |
One assessment of Rotarod performance revealed no impairment at 12 months. |
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 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (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 tyrosine hydroxylase(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 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
Absent
-
Motor Impairment at
Not observed.
No Data
-
Dopamine Deficiency at
No data.
-
Non-Motor Impairment at
No data.
-
α-synuclein Inclusions at
No data.
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities at
No data.
-
Neuronal Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
LRRK2 | LRRK2: Transgenic | Parkinson's Disease | Overtly normal brain structure. Intact neurites. |
No observed behavioral differences from wild-type mice at 10 months of age. |
Parkin KO Rat
Observed
-
Mitochondrial Abnormalities at 11
Alterations in mitochondrial function and protein expression were detected in striatal synapses of 2- to 3-month-old KO rats.
Absent
-
Dopamine Deficiency at
There were no differences in striatal dopamine levels at 4, 6, or 8 months compared with wild-type rats. However, factors involved in dopaminergic transmission, including monoamine oxidase activity, β-phenylethylamine, trace amine-associated receptor 1, and postsynaptic dopamine D2 receptors were altered in the striata of 2-month-old KO rats.
-
Non-Motor Impairment at
-
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.
-
Neuronal Loss at
A small, non-significant reduction in dopaminergic neurons was observed in the substantia nigra at eight months of age.
No Data
-
Neuroinflammation at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
PRKN (parkin) | PRKN (parkin): 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 function and protein expression in striatal synapses. No increase in α-synuclein protein in the striatum or other brain regions. |
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. |
Parkin Q311X Mouse (BAC Tg)
Observed
-
Dopamine Deficiency at 83
Surviving nigral neurons had reduced tyrosine hydroxylase expression. By 19-21 months, striatal concentrations of dopamine and the dopamine metabolite, 3,4-dihydrooxyphenylacetic acid (DOPAC), were decreased compared with non-Tg littermates.
-
Motor Impairment at 70
Behavior was fairly normal at 3 months, but motor abnormalities were measured by 16 months of age, including hypoactivity and deficits in coordination and in motor response to sensory stimuli.
-
Neuronal Loss at 70
Progressive loss of dopaminergic neurons in the substantia nigra. 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
-
α-synuclein Inclusions at
Inclusions were not observed at any age, however, the mice exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in the substantia nigra.
No Data
-
Non-Motor Impairment at
No data.
-
Neuroinflammation at
No data.
-
Mitochondrial Abnormalities at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
PRKN (parkin) | Parkin Q311X | PRKN (parkin): Transgenic | Parkinson's Disease | Degeneration of dopaminergic neurons in the substantia nigra and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein 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. |
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 increased in the cerebellum, as did 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 of α-synuclein aggregates in the brainstem or substantia nigra, but the expression levels of alpha-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 alpha-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
-
Motor Impairment at 23
Reduced spontaneous locomotor activity and skill reported at 3-6 months, as well as modest vocalization deficits at 4-6 months.
-
Mitochondrial Abnormalities at 0
Altered shape, density, and movement of dendritic mitochondria were 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.
Absent
-
Dopamine Deficiency at
Overall striatal levels of dopamine did not significantly differ from levels in wild-type mice at two to three months or eight to nine 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
-
Non-Motor Impairment at
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 | Overtly normal brain structure. Normal numbers of dopaminergic neurons and tyrosine hydroxlase 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 spontaneous locomotor activity and skill at 3-6 months. Modest vocalization deficits at 4-6 months. |
Pink1 KO Rat
Observed
-
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. 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 behaviors.
-
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.
-
Neuronal Loss at 26
Age-related decrease in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra. Twenty-five and 50 percent reduction at 6 months and 8 months, respectively. No change in TH-positive cells in the striatum.
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.
No Data
-
Non-Motor Impairment at
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 in periaqueductal gray, substantia nigra pars compacta, locus coeruleus, nucleus ambiguus, cortex, thalamus, and striatum. 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 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 |
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. |