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) to make PD models more accessible and accelerate PD research. In 2024, the Aligning Science Across Parkinson’s initiative provided additional funding support to expand the collection of characterized models.

This database is not comprehensive and only includes genetically engineered Parkinson’s disease models selected by experts at MJFF. Models were prioritized for inclusion if they met the following criteria: (1) models Parkinson’s disease genetics or pathology, (2) published in peer-reviewed publications, ideally by multiple research teams, and (3) available at a repository for open access. For questions, please email tools@michaeljfox.org.

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+.

Atp13a2-flox Mouse

Observed
  1. X
    Neuroinflammation at 4

    Germline Atp13a2 KO mice exhibit progressively worsening astrogliosis starting as early as 1 month of age, but in mice with adult-onset Atp13a2 KO in the ventral midbrain, astrogliosis and microglial reactivity were present only transiently after AAV-Cre delivery.

  2. X
    Motor Impairment at 39

    Germline Atp13a2 null mice exhibit some motor defects on the open-field test (starting at 9 months of age) and in the tail suspension test (at 18 months of age), but other motor measures (including balance beam and Rotarod performance) did not differ from wild-type mice.

  3. X
    Neuronal Loss at 52

    No cell loss in the substantia nigra pars compacta (SNpc) in germline Atp13a2 null mice by 18 months of age, but in mice with adult-onset Atp13a2 KO in the ventral midbrain (via AAV-Cre delivery), dopaminergic neuronal degeneration in the SN was observed 10 months after injection (i.e., in 12- to 16-month-old mice).

Absent
  • Dopamine Deficiency at

    No differences observed between germline Atp13a2 null mice and wild-type mice in tyrosine hydroxylase levels (western blot) in the striatum or midbrain at 18 months of age.

  • α-synuclein Inclusions at

    α-synuclein pathology absent in germline KO mice at 18 months of age, and also absent in mice with ventral midbrain, adult-onset Atp13a2 deletion.

No Data
  • Non-Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

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DJ-1 KO Rat

Observed
  1. X
    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).

  2. X
    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.

  3. X
    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

  4. X
    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.

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Gba1 D409V KI Mouse (Grabowski)

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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.

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Gba1 D409V KI Mouse (MJFF)

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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.

  4. X
    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.

  5. X
    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.

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Gba1 L444P KI Mouse (JAX)

Observed
  1. X
    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.

  2. X
    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.

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Gba1 L444P KI Mouse (MMRRC)

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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

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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

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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

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LRRK2 R1441C KI Mouse

Observed
  1. X
    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.

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LRRK2 G2019S KI Mouse

Observed
  1. X
    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.

  2. X
    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.

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LRRK2 G2019S Mouse (BAC Tg)

Observed
  1. X
    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).

  2. X
    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.

  3. X
    Neuroinflammation at 8

    Application of α-synuclein fibrils leads to exacerbated responses (more inclusions and greater infiltration of pro-inflammatory monocytes).

  4. X
    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).

  5. X
    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

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LRRK2 G2019S Mouse (Tg)

Observed
  1. X
    Non-Motor Impairment at 45

    Anxiety/depression-like symptoms were observed at 10-12 months of age.

  2. X
    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.

  3. X
    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.

  4. X
    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.

  5. X
    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.

  6. X
    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

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LRRK2 G2019S Rat (BAC Tg)

Observed
  1. X
    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

  2. X
    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.

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Lrrk2 KO Mouse

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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

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Lrrk2 KO Rat

Observed
  1. X
    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.

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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.

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LRRK2 WT Mouse (BAC Tg)

Observed
  1. X
    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.

  2. X
    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.

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MCI-Park Mouse

Observed
  1. X
    Dopamine Deficiency at 5

    Profound loss of evoked dopamine release in the dorsolateral striatum as early as 30 days. In contrast, somatodendritic dopamine release in the SN did not differ between genotypes at 30 days, but was dramatically reduced by 60 days.

  2. X
    Non-Motor Impairment at 2

    Impaired associative learning (Y-maze test) at 30 days . Impaired sleep functions starting at 6 weeks of age, with significantly altered sleep-wake patterns (total, NREM, and REM sleep), increased sleep fragmentation, and altered EEG activity.

  3. X
    Motor Impairment at 6

    Striatal motor learning (adhesive removal test) was impaired starting at 30 days. Rearing in the cylinder testing was impaired at 40 days. Total distance travelled was decreased by 60 days on the open-field test. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride observed.

  4. X
    Mitochondrial Abnormalities at 3

    By 20 days mitochondria were in an oxidative phosphorylation deficit. Altered mitochondria structure, but not mitochondrial density, was observed at 35 days in dopaminergic neurons of the SN. Metabolic reprogramming to a glycolytic-predominant state of mitochondria was indicated by alterations in expression of genes and functional pharmacologic experiments.

  5. X
    Neuronal Loss at 4

    TH expression decreased at 30 days in the dorsal striatum. By age 60 days, TH expression decreased in substantia nigra dopaminergic neurons. No neurodegeneration was observed in axons, cell bodies, or dendritic arbors of SN dopaminergic neurons at 60 days. By 120 to 150 days, neurodegeneration is present and about 40% of SN dopaminergic neurons are lost.

Absent
No Data
  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

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Parkin KO Mouse

Observed
  1. X
    Dopamine Deficiency at 11

    Levels of striatal dopamine and metabolites DOPAC and HVA were normal at 6, 12, 18, and 24 months. In another study, striatal extracellular dopamine was increased, as measured by no-net-flux microdialysis, in 8-9-month-old mice. In a third study, evoked striatal dopamine release was reduced in striatal slices of 2-4-month-old mice.

  2. X
    Non-Motor Impairment at 9

    Novel object recognition was decreased at 4-5 months of age and reduced sociability, increased repetitive behaviors, and deficits in communication were present at 2-3 months of age. Outcomes from the forced swim test, time spent investigating novel odors, latency to find buried food, the Barnes maze test, hot plate test, Morris water maze appear unaffected. 

  3. X
    Motor Impairment at 19

    On the beam traversal task, KO mice displayed deficits starting at 2-4 months of age. General behavior (beam breaks) on the open-field test did not differ at 6, 12, and 18 months of age. Findings on the Rotarod suggest no differences or that KO mice may have enhanced performance. 

  4. X
    Mitochondrial Abnormalities at 7

    Mitochondrial defects begin at 7 weeks. Proteomic analyses reveal differences in ventral midbrain lysates of proteins involved in mitochondrial function. Respiratory and antioxidant capacity, mitophagy, and mitochondrial DNA are affected. Mitochondrial structure appears intact in the brain, but is affected in heart tissue.

Absent
  • α-synuclein Inclusions at

    Inclusions of α-synuclein were not observed in any brain region.

  • Neuroinflammation at

    Spinal cord staining of GFAP did not differ between non-transgenic and parkin KO mice at 130 days of age.

  • Neuronal Loss at

    In the substantia nigra, the number of dopaminergic neurons (as detected by TH staining) did not differ between parkin KO and wild-type mice up to 24 months. Dopaminergic projections in the striatum were also normal.

No Data

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Parkin KO Rat

Observed
  1. X
    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.

  2. X
    Mitochondrial Abnormalities at 14

    Alterations in mitochondrial protein expression in synaptic and nonsynaptic striatal samples of 3-month-old KO rats.

  3. X
    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.

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Parkin Q311X Mouse (BAC Tg)

Observed
  1. X
    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.

  2. X
    Non-Motor Impairment at 68

    Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.

  3. X
    Non-Motor Impairment at 71

    Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.

  4. X
    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.

  5. X
    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.

  6. X
    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.

  7. X
    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.

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Parkin S65A KI Mouse

Observed
  1. X
    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.

  2. X
    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.

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PINK1 G309D (PINK1-/-) Mouse (KI)

Observed
  1. X
    Dopamine Deficiency at 39

    Decreased dopamine concentration in the striatum by 9 months of age.

  2. X
    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.

  3. X
    Motor Impairment at 70

    At 16 months of age Pink1-/- mice exhibited decreased spontaneous locomotor activity. Strength and coordination were intact.

  4. X
    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

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PINK1 KO Mouse

Observed
  1. X
    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.

  2. X
    Motor Impairment at 23

    Reduced spontaneous locomotor activity and skill reported at 3-6 months.

  3. X
    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.

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Pink1 KO Rat

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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.

  4. X
    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.

  5. X
    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.

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Thy1-αSyn “Line 61” Mouse

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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.

  4. X
    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.

  5. X
    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.

  6. X
    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.

  7. X
    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

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Vps35 p.D620N KI Mouse

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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.

  4. X
    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.

  5. X
    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.

  6. X
    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

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α-synuclein A30P/A53T Mouse (Tg)

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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.

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α-synuclein A53T Mouse (Tg)

Observed
  1. X
    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.

  2. X
    Non-Motor Impairment at 50

    At 11–12 months, spatial memory was impaired as assessed by the Barnes circular maze.

  3. X
    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.

  4. X
    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.

  5. X
    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.

  6. X
    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

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α-synuclein A53T Mouse (Tg) on SNCA KO

Observed
  1. X
    Non-Motor Impairment at 7

    By 3 months of age, the mice develop gastrointestinal dysfunction. By 6 weeks of age, mice exhibited less anxiety-like behavior, and by 22 weeks of age they exhibited greater depression-like behavior and less spontaneous behavior.

  2. X
    Motor Impairment at 6

    By 6 months of age, homozygous mice became hypoactive, traveling less distance. This was not attributed to changes in exploratory behavior caused by anxiety. As early as 6 weeks of age, differences in performance on the accelerating Rotarod were seen. Impairments were also observed on the pole test and hindlimb clasping test, but not the inverted grid.

Absent
  • Dopamine Deficiency at

    No differences in striatal dopamine concentrations or in the 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.

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α-synuclein E46K Rat (BAC Tg)

Observed
  1. X
    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.

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α-synuclein KO Mouse

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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.

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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.

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