Table 3.

Mouse models of PD based on familial PD gene mutations and/or the exhibition of an informative phenotype with respect to PD pathogenesis and/or progression

Category	Gene	Gene Product	Animal Model	Protein Accumulation/ Aggregation	Oxidative Stress/Altered Mitochondria	Dopaminergic Cell Death	Motor Phenotype	Dopamine Metabolism/ Homeostasis Alterations
Proteasome Models	park2 knockout	Parkin	knockout	no [69;74;187;188] but ↑p53 mRNA and protein levels [189] ↑tau levels in geriatric mice but no inclusion formation [125]	mitochondrial dysfunction; ↑protein and lipid peroxidation [100], ↓mitochondria complex I activity [74], ↑abnormal glial mitochondria [101], ↑GSH may represent compensation to ↑oxidant stress [190]	no [68] but loss of TH⁺ catecholaminergic neurons in locus coeruleus [188], ↓ TH⁺ SN neurons in geriatric mice [125]	↓coordination [68], ↓startle response [188]	↑striatal DA, ↓striatal synaptic excitability [68], ↑midbrain DA levels, ↑striatal DA receptor binding [187], ↓norepinephrine [188], ↓striatal DAT and VMAT levels, [190]
	park2 dominant negative mutant	Parkin	mutant transgenic	parkin substrate accumulation in SN TH⁺ neurons [191]	not reported	no [191]	↓motor activity and ↓coordination responsive to L-DOPA treatment [191]	↑striatal DA [191]
	park2 truncated mutant Q311X	Parkin	BAC transgenic	accumulation of proteinase K- resistant α-syn in SN [192]	3-nitrotyrosine associated with accumulated α-syn [192]	age-dependent DA neuron degeneration in SN [192]	progressive ↓in motor activity [192]	↓striatal DA and metabolite levels, loss of striatal DA nerve terminals [192]
	psmc1 conditional knockout in nigrostriatal pathway	26S proteasome subunit	conditional knockout in SN and forebrain	intraneuronal inclusions containing α-syn, ubiquitin, mitochondria [64]	GFAP activation [64]	extensive loss of TH⁺ neurons and death by 3–4 months [64]	not reported	severe ↓striatal DA content [64]
	uchl1 I93M mutation	UCH-L1	transgenic	↑ SDS- insoluble UCH- L1 [67]	not reported	loss of DA SN neurons [67]	reduced locomotor activity [67]	↓striatal DA [67]
Dopamine Metabolism Models	drd2 knockout	DA D2 receptor	knockout	insoluble α-syn⁺ ubiquitin LB-like inclusions in TH⁺ SN neurons [78]	↑oxidative stress, ↑lipid peroxidation [78]	loss of TH⁺ SN neurons [193]	bradykinesia, ↓locomotor activity, abnormal gait/posture [76]	abnormal synaptic plasticity [77], ↑striatal DA levels, DA terminal density and DA activity [193]
	th knockout	TH	knockout	N/A	N/A	N/A	N/A	L-DOPA administration rescues perinatal lethality [79;80]
	maob wildtype, astrocyte inducible	MAOB	inducible	not reported	↓mitochondria complex I activity, ↑oxidant levels, gliosis [85]	progressive degeneration of TH⁺ SN neurons [85]	↓spontaneous locomotor activity [85]	reduced striatal DA [85]
	vmat2 hypomorphic allele	VMAT2	95% knockdown	α-syn accumulation in aged mice [91]	↑cysteinyl DOPAC adducts, 3- nitrotyrosine formation [91]	TH⁺ SN cell neurodegeneration in aged mice [91]	progressive ↓motor coordination (L-DOPA responsive), ↓locomotor acitivity (L- DOPA responsive) [91]	↓striatal DA [90], ↑DA turnover, progressive ↓striatal monoamines, ↓DAT levels [91]
Mitochondria Models	park6 knockout	PINK1	knockout	not reported	mitochondrial and respiratory deficits [99], enlarged mitochondria; age-dependent impairment of mitochondrial respiration [126]	no	progressive weight loss accompanied by ↓locomotion [99]	↓striatal DA release but no change in striatal DA or metabolite levels, impaired corticostriatal plasticity rescued by L-DOPA [98], progressive ↓striatal DA with age [99]
	park7 knockout	DJ-1	knockout	no [194], ↑autophagic activity may prevent protein accumulation [129]	dysfunctional skeletal muscle mitochondria may explain motor deficit [128], no change in oxidatively modified proteins [194] altered mitochondrial morphology, ↑ROS [129]	no [194]	progressively ↓locomotion and grip strength; gait impairment [194;195]	↑DA reuptake, ↑striatal DA [194]
	tfam conditional knockout in DA neurons	Tfam	conditional knockout in DA neurons	intraneuronal inclusions with mitochondrial components [109]	abnormal mitochondrial morphology [109]	DA nerve cell death [109]	tremor, rigidity (L-DOPA responsive) [109]	severely ↓nigrostriatal DA [109]
Synphilin-1 Models	sncaip wildtype and R621C	synphilin-1	transgenic	ubiquitin inclusions in cerebellum, synphilin-1 aggregation in various brain regions (SN, etc) [114]	mitochondrial swelling [114]	no but Purkinje cell degeneration [114]	↓motor performance and motor skill learning [114]	↑nigrostriatal DA levels [114]
Synphilin-1 Models	sncaip wildtype	synphilin-1	transgenic	synphilin-1 + ubiquitin insoluble aggregates [110]	unknown	no [110]	↓motor function and step length [110]	unknown
LRRK2 Models	park8 knockout	LRRK2	knockout	no brain pathology but extensive α-syn and ubiquitin aggregates in kidneys with autophagy lysosome dysfunction [119]	inflammation and oxidative damage in kidneys [119]	no loss of TH⁺ SN neurons but apoptotic cell death in kidneys [119]	not reported	no change in striatal DA [119]
	park8 R1441C	LRRK2	knock-in	no [196]	no change in GFAP levels detected [196]	no [196]	no [196]	DA D2 receptor- mediated impairments, ↓DA neurotransmission [196]
	park8 wildtype	LRRK2	BAC transgenic	no [118]	not reported	no [118]	hyperactive, ↑motor function [118]	↑striatal DA release [118]
	park8 R1441G	LRRK2	BAC transgenic	↑phospho-tau, axonal pathology in nigrostriatal pathway [117]	no spinal gliosis [117]	loss of TH⁺ dendrites in SN and ↓SN neuron size [117]	progressive ↓locomotor activity (L- DOPA responsive) [117]	↓DA release [117]
	park8 G2019S	LRRK2	BAC transgenic	no [118]	not reported	no [118]	no [118]	progressive ↓striatal DA, DA release and uptake [118]
Multi-gene Models	park8 wildtype/snca A53T, park8 G2019S/snca A53T and park8 kinase dead/snca A53T	LRRK2 + α-synuclein	LRRK2 transgenic + mutant α-syn transgenic	↑somal and insoluble α-syn⁺ ubiquitin aggregates vs. A53T transgenic alone [137]	↑gliosis, abnormal mitochondrial structure and function (vs. A53T alone) [137]	no but loss of striatal and cortical neurons (accelerated vs. A53T alone) [137]	not reported	not reported
	park8 knockout/snca A53T	LRRK2 + α-synuclein	LRRK2 knockout + mutant α-syn transgenic	↓ accumulation of α-syn oligomers (vs A53T alone) [137]	no significant gliosis (vs A53T alone) [137]	no but ↓neurodegeneration vs. A53T alone [137]	not reported	not reported
	park2 knockout/doubly mutated A30P/A53T α-synuclein	Parkin + α-synuclein mouse TH promoter	Parkin knockout + mutant α-syn transgenic	no [74]	↑mitochondrial structural alterations and ↓complex I activity vs. non- transgenic mice [74]	no [74]	no [74]	not reported
	park2 knockout/snca A53T	Parkin +α-synuclein	Parkin knockout + mutant α-syn transgenic	not increased from A53T alone [72]	not reported	not increased from A53T alone [72]	not increased from A53T alone[72]	not increased from A53T alone [72]
	park2 knockout/doubly mutated A30P/A53T α-synuclein	Parkin + α-synuclein chicken beta actin promoter	Parkin knockout + mutant α-syn transgenic	no [74]	↑mitochondrial structural alterations and ↓complex I activity vs. non- transgenic mice [74]	no [74]	no [74]	not reported
	park2 knockout/snca A30P	Parkin/α-synuclein	Parkin knockout + mutant α-syn transgenic	similar accumulation of insoluble S129 phospho-α-syn; ↓ubiquitin aggregation (vs. A30P alone) [197]	not reported	not reported	delayed onset of motor dysfunction (vs. A30P alone) [197]	not reported
	park2, park7, and park6 knockout	Parkin/DJ- 1/PINK1	triple knockout	no [71]	unknown	no [71]	not reported	no [71]
	sncaip wildtype and snca A53T	synphilin- 1/α-synuclein	double transgenic	delayed synucleinopathy (vs. A53T alone) [138]	↓astrogliosis (vs. A53T alone) [138]	no but ↓axonal degeneration (vs. A53T alone) [138]	↓motor defects (vs. A53T alone) [138]	not reported