Table 1 Summary of LRRK2 mutant KI mouse models with PD-relevant phenotypes
From: LRRK2 mutant knock-in mouse models: therapeutic relevance in Parkinson's disease
Mutation | Striatal physiology | Motor and non-motor phenotypes | Mitochondrial defects | Autophagy-lysosomal defects | Synucleinopathy/tauopathy | References |
|---|---|---|---|---|---|---|
R1441C | No DA loss. Absence of AMPH-induced synaptic DA release | Absence of AMPH-induced increase in locomotor activity | NA | NA | No aggregation of α-synuclein, tau and ubiquitin | [123] |
Absence of quinpirole-induced reduction in locomotor activity | ||||||
Aberrant synaptic PKA activity in dSPN | NA | NA | NA | NA | [124] | |
Abnormal reorganization of synaptic receptor proteins in dSPN | NA | NA | NA | NA | [134] | |
Reduction of evoked DA release | Impaired iSPN-associated motor learning defects | NA | NA | NA | [136] | |
Decreased excitability of iSPN | Â | Â | Â | Â | Â | |
NA | Impaired fine motor tasks and reduced locomotion | NA | NA | NA | [143] | |
Reduced olfactory sensitivity | ||||||
R1441G | No DA loss. Lower DA uptake induced by reserpine | Reserpine-induced impairment in locomotor activity | NA | NA | NA | [125] |
NA | Rotenone-induced motor deficits in aged mice | Complex I deficiency after long-term treatment with rotenone | NA | NA | [142] | |
NA | NA | Abnormal mitochondrial morphology. Impaired Erk-Drp1 signalling under FCCP | Impaired clearance of damaged mitochondria | NA | [159] | |
NA | NA | NA | Aberrant accumulation of CMA-specific proteins in the brain: LAMP2A and HSPA8/HSC70 | Increased accumulation of α-synuclein oligomers in brains of aged mice | [162] | |
G2019S | NA | Hyperkinetic behaviour resistant to aging-associated motor decline | NA | NA | NA | [145] |
Alterations in synaptic proteins (DAT, VMAT2) | NA | NA | NA | Increased accumulation of pSer129 α-synuclein in aged mice | [128] | |
No changes in basal DA level in the striatum | ||||||
Age-dependent reduction in basal DA level. Absence of AMPH-induced synaptic DA release |  | Morphological defects in mitochondria in striatum and other brain regions | NA | Increased tau puncta formation. Increased phosphorylated tau. No α-synuclein pathology | [126] | |
Elevated DA and glutamate transmission in young mice that otherwise decrease with age | Reduction in exploratory behaviour with age | NA | NA | NA | [137] | |
Aberrant D2-receptor responses | ||||||
NA | NA | NA | Impaired mitophagy rescued with LRRK2 kinase inhibitor (GSK2578215A) | Impaired α-synuclein degradation in primary neurons; phenotype rescued with LRRK2 kinase inhibitor (GSK2578215A) | [160] | |
NA | NA | NA | NA | Greater nigral degeneration and pSer129 aggregates in brains of aged KI mice induced by stereotactic injection of AAV2/9-A53T-α-synuclein | [183] | |
Reduction of evoked DA release | NA | NA | NA | NA | [136] | |
NA | NA | NA | Altered expression of autophagy proteins (LAMP2, mTOR, TFEB, GBA1) | NA | [164] | |
NA | NA | NA | Impaired basal mitophagy that was  rescued with LRRK2 kinase inhibitor (GSK3357679A) | NA | [165] | |
NA | NA | NA | Impaired autophagosome transport | NA | [166] |