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.

18 Models

Name Other Names Strain Name Genetic Background Gene Mutation Modification Info Modification Disease Neuropathology Behavior/Cognition Other Phenotype Availability Primary Paper Visualization
Rat Models (6)
DJ-1 knockout rat LEH-Park7tm1sage Long Evans Hooded PARK7 (DJ1) Disruption of the DJ-1 gene by zinc finger nuclease (ZFN) technology. ZFNs were engineered to bind to a recognition sequence in exon 5 of PARK7 and cleave DNA. PARK7 (DJ1): Knock-Out Parkinson's Disease Age-related decrease in dopaminergic neurons in the substantia nigra; more than 50 percent reduction at eight months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels. Abnormalities in gait and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride. Weak hind limbs with some dragging. Coordination largely intact. No increase in mortality up to 8 months of age. Available through Horizon Discovery (formerly Sage Labs). Cat #TGRL4830; Live. Dave et al., 2014 Yes
Line 10681, hBAC G2019S-LRRK2, LRRK2 G2019S rat NTac:SD-Tg(LRRK2*G2019S)571CJLi Sprague-Dawley LRRK2 LRRK2 G2019S BAC construct carrying the human gene Lrrk2 with the G2019S mutation. 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. Available through Taconic, Cat# 10681, Live. West et al., 2014 Yes
Lrrk2 knockout rat LEH-Lrrk2tm1sage Long Evans Hooded LRRK2 Zinc finger nuclease (ZFN) technology was used to generate a deletion of 10 base pairs in exon 30 of the rat Lrrk2 gene. This resulted in a frameshift and a premature stop codon in the same exon. 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 data. Abnormalities in peripheral organs, including the kidney, liver, and lung. Available through Horizon (formerly Sage Labs), Cat #TGRL4620, Live. Baptista et al., 2013, Ness et al., 2013 Yes
Park2 KO, Parkin knockout rat LEH-Park2TM1sage Long Evans Hooded PRKN (parkin) The rat Park2 gene was disrupted using zinc finger nuclease (ZFN) technology. The targeted ZFN created a DNA strand break in exon 4 of Park2. Repair of this break created a deletion of five base pairs, leading to a frame shift and the creation of a premature stop codon. PRKN (parkin): Knock-Out Parkinson's Disease Minimal pathology. A non-significant reduction in dopaminergic neurons in the substantia nigra. No differences in striatal dopamine levels. Parkin KO rats exhibit normal behavior. Available through Horizon Discovery (formerly Sage Labs); TGRL4760; Live. Dave et al., 2014 Yes
Pink1 knockout rat, PARK6 KO rat LEH-Pink1tm1Sage-/- Long Evans Hooded PINK1 The rat Pink1 gene was disrupted using zinc finger nuclease (ZFN) technology. The ZFNs were engineered to bind to a recognition site in exon 4 of Pink1 and cleave the DNA. When the resulting double strand break was repaired, a deletion of 26 base pairs was created. This deletion lead to a frameshift and the creation of a premature stop codon. PINK1: Knock-Out Parkinson's Disease Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Striatal dopamine and serotonin levels elevated 2-3-fold over wild-type levels. Abnormalities in gait, coordination, and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride, paw slips on balance bean. Weak hind limbs with dragging. Heavier than wild-type rats at 4, 6, and 8 months of age. No increase in mortality. Available through Horizon Discovery (formerly Sage Labs), Cat# TGRL4690; Live. Dave et al., 2014 Yes
α-synuclein (E46K) rat, founder line 70, Human α-synuclein E46K rat, E46K aSyn Rat, Alpha-synuclein E46K Rat (BAC Tg) NTac:SD-Tg(SNCA*E46K)70CJLi Sprague-Dawley SNCA SNCA E46K A bacterial artificial chromosome (BAC) was used to introduce human α-synuclein with the E46K mutation. 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. Viable and fertile. Available through Taconic Cat #10679; Cryopreserved. Cannon et al., 2013 Yes
Mouse Models (12)
BAC Lrrk2-G2019S, FLAG-Lrrk2-G2019S, BAC-Lrrk2-G2019S, LRRK2 G2019S BAC Tg Mouse (Yue) B6.Cg-Tg(Lrrk2*G2019S)2Yue/J A BAC construct was injected into B6C3 F1 oocytes. Founder line 2 was established and maintained by breeding to C57BL/6J inbred mice. LRRK2 LRRK2 G2019S A bacterial artificial chromosome (BAC) containing the entire mouse Lrrk2 gene was modified to include the G2019S mutation. The BAC (~240 kb) contained the murine Lrrk2 promoter region (~35 kb) and a FLAG-tag downstream of the start codon. 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. Mutant Lrrk2 protein purified from mouse brain had increased kinase activity. Age-dependent electrophysiological changes in the hippocampus including increased basal synaptic efficiency though a postsynaptic mechanism and decreased LTD. Available through The Jackson Lab, Stock# 012467, Live. Li et al., 2010 Yes
G2019S-LRRK2 (line 340), G2019S-LRRK2 transgenic, LRRK2 G2019S Tg Mouse (Dawson/Moore) B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J Transgene introduced into C57BL/6J x C3H/HeJ embryos. Founder mice were bred with C57BL/6J mice. LRRK2 LRRK2 G2019S Transgenic mice overexpress full-length mutant human LRRK2 with the G2019S mutation. Transgene expression is driven by a hybrid CMVe-PDGFβ promoter. 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 neurons and accumulation of autophagic vacuoles. No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex. No differences in body weight or survival. Available through The Jackson Laboratory, Stock# 016575, Cryopreserved. Ramonet et al., 2011 Yes
R26-LRRK2; R26-LRRK2+/+, R26-LRRK2+/+/DAT-Cre mice, ROSA26-LRRK2(R1441C), R1441C LRRK2 Tg Mouse (Moore) STOCK Gt(ROSA)26Sortm1(LRRK2*R1441C)Djmo/J R26-LRRK2 mice were generated from 129/SvJ ES cells microinjected into C57Bl/6J mouse blastocysts. Chimeras were bred with C57Bl/6J mice and maintained on a mixed genetic background (129/SvJ and C57Bl/6J). BAC-DAT-iCRE mice were maintained on a C57Bl/6J background. LRRK2 LRRK2 R1441C Full-length human LRRK2 with the R1441C mutation was targeted to the endogenous ROSA26 locus by homologous recombination. Cre-mediated excision of the transcriptional termination sequence allows for transgene expression. The Cre line expressed Cre-recombinase driven by the dopamine transporter (DAT) promoter derived from a BAC construct containing the entire mouse DAT (slc6) gene. 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. Fertile. Normal survival. No overt olfactory deficits. Available through The Jackson Laboratory, Stock# 022793, Cryopreserved. Tsika et al., 2014 Yes
WT-OX, LRRK2 WT BAC, WT LRRK2 Mouse (BAC Tg), WT LRRK2 BAC Tg Mouse (Li) FVB/N-Tg(LRRK2)1Cjli/J BAC injected into fertilized FVB zygotes. Founder mice bred with FVB/N inbred mice for many generations, and then with FVB/NJ inbred mice. LRRK2 A 188 kb human bacterial artificial chromosome (BAC) containing the entire human LRRK2 gene, with 29 kb upstream and 42 kb downstream. LRRK2: Transgenic Parkinson's Disease Overtly normal brain structure. Intact neurites. No observed behavioral differences from wild-type mice at 10 months of age. Available through The Jackson Laboratory, Stock# 009610, Live. Li et al., 2009 Yes
PARK2-Q311X, Parkin-Q311X(A), Parkin-Q311X (line A), Parkin Q311X BAC Tg Mouse (Yang) FVB/NJ-Tg(Slc6a3-PARK2*Q311X)AXwy/J The BAC was microinjected into fertilized FVB/NJ zygotes, then bred to FVB/NJ inbred mice. PRKN (parkin) Parkin Q311X Bacterial artificial chromosome (BAC)-mediated expression of mutant parkin in dopaminergic neurons. The promoter and regulatory regions of Slc6a3 (dopamine transporter) drive expression of parkin with the truncation mutation Q311X. The protein has an N-terminal Flag-tag. Two copies of the transgene integrated in tandem. 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. Available through The Jackson Laboratory, Stock# 009090, Live. Lu et al., 2009 Yes
Pink1-, Pink1-deficient mouse, PARK6 mouse, Pink1-/-, PINK1 G309D (PINK1-) KI Mouse (Auburger) B6;129-Pink1tm1Aub/J The vector was introduced into a 129/SvEV-derived embryonic stem cell line. Resulting chimeric mice were bred and maintained on a pure 129 background. PINK1 Pink1 G309D A targeting vector was used to introduce the G309D mutation into exon 4 at the orthologous mouse locus. A floxed neomycin cassette in the inverse orientation was inserted into intron 5 via homologous recombination. 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). Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination. Electrophysiological abnormalities, including altered glutamergic activity in midbrain dopaminergic neurons and early hypersynchrony in motor cortex. Medium spiny neurons in striatal slice exhibit giant GABAergic currents. Hyperactive subthalamic nucleus neurons, indicated by spontaneous bursts instead of single spikess Available through The Jackson Laboratory, Stock# 013050, Cryopreserved. Gispert et al., 2009 Yes
Pink1 KO, Pink1 knockout mouse, Pink1-, Pink1-/-, PINK1 KO Mouse (Shen) B6.129S4-Pink1tm1Shn/J Congenic C57BL/6J. The construct was introduced into 129S4/SvJae-derived J1 embryonic stem cells, which were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to generate homozygotes and then backcrossed to C57BL/6J for >7 generations. PINK1 A targeting vector containing a PGK-Neo cassette was used to disrupt exons 4 through 7 of the endogenous PINK1 gene. This creates a nonsense mutation at the beginning of exon 8; truncated RNA is degraded. PINK1: Knock-Out Parkinson's Disease Overtly normal brain structure. Normal numbers of dopaminergic neurons in the substantia nigra at 8-9 months of age. Neuronal morphology grossly intact. No data. Plasticity abnormalities. Reduced LTP and absent LTD in response to high frequency stimulation; reversed by dopamine agonists. Available through The Jackson Laboratory, Stock# 017946; Live. Kitada et al., 2007 Yes
hm2α-SYN-39, HM2, hm2α-SYN, human doubly mutated α-synuclein, A30P/A53T aSyn Mouse (Tg), A30P/A53T aSyn Tg Mouse (Richfield), alpha-synuclein A30P/A53T Mouse (Tg), B6J(239) C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J Transgene injected into C57/BL6 oocytes, then bred to C57/BL6J. SNCA SNCA A30P, SNCA A53T This model expresses a transgene encoding human α-synuclein with two mutations (A30P and A53T) driven by 9kb rat tyrosine hydroxylase (TH) promoter. SNCA: Transgenic Parkinson's Disease No dopaminergic cell loss. 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. No weight differences compared to non-Tg. Available through The Jackson Laboratory, Stock# 008239, Live. Richfield et al., 2002 Yes
G2-3(A53T), PrPsynA53T, A53TαS Tg mice (line G2-3), MoPrP-Huα-Syn(A53T), Hualpha-Syn(A53T), A53T aSyn Tg Mouse (Lee), alpha-synuclein A53T Mouse (Tg) B6.Cg-2310039L15RikTg(Prnp-SNCA*A53T)23Mkle/J. Formerly: B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J Established as C3H/HeJ x C57BL6/J hybrids, then maintained by backcrossing to C57Bl6/J. SNCA SNCA A53T Transgene comprising human α-synuclein with the A53T mutation was inserted downstream of the mouse prion protein (PrP) promoter. SNCA: Transgenic Parkinson's Disease No overt neuronal loss. No change in striatal dopamine levels. 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. Premature death. Available through The Jackson Laboratory, Stock# 006823, Live. Lee et al., 2002 Yes
PAC-Tg(SNCA-A53T) +/+; Snca-/-, dbl-PAC-Tg(SNCAA53T);Snca-/-, A53T aSyn Tg Mouse (Nussbaum), Alpha-synuclein A53T Mouse (Tg) on SNCA KO FVB;129S6-Sncatm1Nbm Tg(SNCA*A53T)1Nbm Tg(SNCA*A53T)2Nbm/J The PAC transgene was injected into FVB/N oocytes and founder mice bred to FVB/N. The knockout mice were made in a 129S6/SvEvTac background. SNCA SNCA A53T In this double-transgenic model, one parental line expresses mutant human α-synuclein (A53T mutation) via a 146 kb P1 artificial chromosome (PAC) containing full-length human SNCA gene and 34 kb upstream sequence. The other line is an Snca knockout line generated by replacing exons 4 and 5 with a neomycin resistance cassette. 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. Gastrointestinal dysfunction (e.g., reduced fecal mass, reduced colonic motility, prolonged whole-gut transit time). α-synuclein–positive aggregates in enteric nervous system. No difference in body weight. No olfactory deficits. No difference in autonomic regulation of heart rate. Available through The Jackson Laboratory, Stock #010799; Live. Kuo et al., 2010, Cabin et al., 2002 Yes
Snca KO, Snca -/-, Snca KO Mouse (Nussbaum), Alpha-synuclein KO Mouse Inbred 129/SvEvTac background. SNCA The mouse Snca gene was disrupted using a targeting vector that replaced exons 4 and 5 with the neomycin resistance gene. 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. Microglial abnormalities. Reduced cardiolipin content in the brain. Some mitochondrial abnormalities. Unknown. Cabin et al., 2002 Yes
Sncaflox(neo), SNCAflox delta neo, Snca conditional knockout, SNCA KO Mouse (Buchman), Alpha-synuclein KO Mouse (Conditional) B6(Cg)-Sncatm1.1Vlb/J C57BL/6J SNCA A targeting vector containing a FRT site-flanked neomysin cassette and a loxP site was inserted downstream of exon 2 and another loxP site was inserted upstream of exon 2. Flp-mediated recombination removed the FRT-flanked neo cassette, leaving exon 2 floxed. When bred to Cre-expressing mice, the resulting offspring have the first coding exon deleted in Cre-expressing tissues. SNCA: Conditional Knock-out Parkinson's Disease No data. No data. Available through The Jackson Laboratory, Stock #025636, Live. Ninkina et al., 2015 Yes

18 Visualizations

Phenotypes Examined

  • Dopamine Deficiency
  • α-synuclein Inclusions
  • Neuroinflammation
  • Motor Impairment
  • Mitochondrial Abnormalities
  • Cognitive Dysfunction
  • Neuronal Loss

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
  1. X
    Motor Impairment at 17

    Abnormalities in gait and strength. As early as four months of age, KOs have abnormal paw positioning and a shorter stride. Overall decrease in muscle tone, particularly in the hind-limb extensor, leading to dragging hind limbs in some animals.

  2. X
    Neuronal Loss at 26

    Age-related decrease in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra. 25 and 50 percent reduction at six months and eight months, respectively. No change 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
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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; more than 50 percent reduction at eight months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels.

Abnormalities in gait and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride. Weak hind limbs with some dragging. Coordination largely intact.

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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 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
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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.

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LRRK2 G2019S Mouse (Tg)

Observed
  1. X
    Mitochondrial Abnormalities at 74

    At 17-18 months of age, the hemizygous mice exhibited abnormally high levels of condensed mitochondria in striatal neurons.

  2. X
    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.

  • Neuroinflammation at

    At around 2 years of age, the mice did not exhibit abnormalities in GFAP in the ventral midbrain, striatum, or cerebral cortex, compared to non-Tg controls.

  • Motor Impairment at

    No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex.

No Data
  • Cognitive Dysfunction at

    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 neurons and accumulation of autophagic vacuoles.

No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex.

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LRRK2 G2019S Rat (BAC Tg)

Observed
  1. X
    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
  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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.

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LRRK2 KO Rat

Observed
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.

  • 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.

  • Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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 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 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).

  • 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.

  • Cognitive Dysfunction 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.

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LRRK2 WT Mouse (BAC Tg)

Observed
Absent
  • Motor Impairment at

    Not observed.

No Data
  • Dopamine Deficiency at

    No data.

  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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.

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Parkin KO Rat

Observed
Absent
  • Dopamine Deficiency at

    There were no differences in striatal dopamine levels at 4, 6, or 8 months compared to wild-type rats.

  • α-synuclein Inclusions at

    There was no increase in α-synuclein protein in the striatum or any other brain region assessed.

  • Motor Impairment at

    Parkin KO rats did not have behavioral deficits at any of the ages tested (4, 6, 8 months). Motor functioning, including gait performance on the Rotarod, was intact.

  • 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.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PRKN (parkin) PRKN (parkin): Knock-Out Parkinson's Disease

Minimal pathology. A non-significant reduction in dopaminergic neurons in the substantia nigra. No differences in striatal dopamine levels.

Parkin KO rats exhibit normal behavior.

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Parkin Q311X Mouse (BAC Tg)

Observed
  1. X
    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.

  2. X
    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.

  3. X
    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
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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.

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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
    Motor Impairment at 70

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

  3. 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
  • 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
  • Neuroinflammation at

    No data.

  • Cognitive Dysfunction at

    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).

Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination.

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PINK1 KO Mouse

Observed
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.

  • Mitochondrial Abnormalities at

    No overt mitochondrial morphological defects.

  • 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.

  • Motor Impairment at

    No data.

  • Cognitive Dysfunction 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 in the substantia nigra at 8-9 months of age. Neuronal morphology grossly intact.

No data.

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Pink1 KO Rat

Observed
  1. X
    Motor Impairment at 17

    Abnormalities in gait, coordination, and strength. As early as four months of age, KO’s have abnormal paw positioning and a shorter stride. By 8 months, they exhibit 3-5-fold more foot slips on the balance beam. Overall decrease in muscle tone, particularly in the hind limb extensor, leading to dragging hind limbs.

  2. X
    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

    Striatal dopamine level was increased 2-3 fold in Pink1 KO rats compared with 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 tested.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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. Striatal dopamine and serotonin levels elevated 2-3-fold over wild-type levels.

Abnormalities in gait, coordination, and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride, paw slips on balance bean. Weak hind limbs with dragging.

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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.

Absent
  • α-synuclein Inclusions at

    Inclusions were not observed at any age. Diffuse α- synuclein protein was both cytoplasmic and nuclear.

  • Neuronal Loss at

    Not observed.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A30P, SNCA A53T SNCA: Transgenic Parkinson's Disease

No dopaminergic cell loss. 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.

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α-synuclein A53T Mouse (Tg)

Observed
  1. 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.

  2. 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.

  3. X
    Motor Impairment at 40

    These mice develop severe motor impairment starting around 9-16 months of age. The deficits start out with mild hyperactivity and progress to a wobbling movement, decreased activity, and ultimately paralysis and death.

Absent
  • Dopamine Deficiency at

    In symptomatic G2-3 mice, striatal dopamine and metabolites DOPAC and HVA were comparable to levels measured in non-Tg mice.

  • Neuronal Loss at

    Overt neuronal loss was not reported in these mice.

No Data
  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A53T SNCA: Transgenic Parkinson's Disease

No overt neuronal loss. No change in striatal dopamine levels. 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.

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α-synuclein A53T Mouse (Tg) on SNCA KO

Observed
  1. X
    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.

  • Cognitive Dysfunction 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.

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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
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction 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.

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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
  • Cognitive Dysfunction at

    Learning and memory appeared intact at 6-10 months of age, based on performance in the Morris water maze and in 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.

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α-synuclein KO Mouse (Conditional)

Observed
Absent
No Data
  • Dopamine Deficiency at

    No data.

  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

  • Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    Unknown.

  • Neuronal Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA: Conditional Knock-out Parkinson's Disease

No data.

No data.

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