Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson's disease and Dementia with Lewy bodies.

GBA is the major risk gene for Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB), two common α-synucleinopathies with cognitive deficits. We investigated the role of mutant GBA in cognitive decline by utilizing Gba (L444P) mutant, SNCA transgenic (tg), and Gba-SNCA double mutant mice. Notably, Gba mutant mice showed early cognitive deficits but lacked PD-like motor deficits or α-synuclein pathology.

Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice.

Auxilin (DNAJC6/PARK19), an endocytic co-chaperone, is essential for maintaining homeostasis in the readily releasable pool (RRP) by aiding clathrin-mediated uncoating of synaptic vesicles. Its loss-of-function mutations, observed in familial Parkinson's disease (PD), lead to basal ganglia motor deficits and cortical dysfunction. We discovered that auxilin-knockout (Aux-KO) mice exhibited impaired pre-synaptic plasticity in layer 4 to layer 2/3 pyramidal cell synapses in the primary visual cortex (V1), including reduced short-term facilitation and depression.

Apoptotic Factors and Mitochondrial Complexes Assist Determination of Strain-Specific Susceptibility of Mice to Parkinsonian Neurotoxin MPTP.

Identification of genetic mutations in Parkinson's disease (PD) promulgates the genetic nature of disease susceptibility. Resilience-associated genes being unknown till date, the normal genetic makeup of an individual may be determinative too. Our earlier studies comparing the substantia nigra (SN) and striatum of C57BL/6J, CD-1 mice, and their F1-crossbreds demonstrated the neuroprotective role of admixing against the neurotoxin MPTP.

Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson's disease.

Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson's disease (PD). Here, we utilized auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD.