Objective: To evaluate the role of auxilin in the pathogenesis of Parkinson’s disease (PD).

Background: Auxilin or DNAJC6, a brain-specific co-chaperone plays central role in uncoating clathrin-coated vesicles to facilitate synaptic vesicle endocytosis and recycling. Loss-of-function recessive mutations of auxilin (PARK19) cause early-onset PD though the mechanisms are still elusive. In this study, we demonstrate that homozygous auxilin KO mice, which were earlier shown to have synaptic endocytosis defects, develop age-related parkinsonism.

Method: Longitudinal motor behavior evaluation was performed on sex matched auxilin KO and wildtype (WT) mice from 3 to 15 months of age. Striatal dopamine depletion, nigral α-synuclein aggregation and dopaminergic neuronal loss, and neuroinflammation were also assessed. Proteomic analysis of whole brain synaptosomes was performed to evaluate the key proteins and pathways that are effected in auxilin KO mice.

Results: Behavior evaluation revealed PD-like motor deficits in auxilin KO mice which were progressive, with no abnormalities at 3 months (presymptomatic) but worsen after 9 months (symptomatic) with tremors at 12-15 months of age. This was accompanied by age-dependent decline of dopamine levels in the dorsal striatum. Loss of nigral dopaminergic neurons, a neuropathological hallmark of PD, along with neuroinflammation was also seen at the symptomatic stage, but not presymptomatically. Evidence for dopamine accumulation in the striatal projections of these neurons in the presymptomatic phase provide insights to the early pathomechanisms. Free cytosolic dopamine is known to be toxic causing oxidative stress, protein adducts and α-synuclein aggregation. In pursuant to this, auxilin KO mice exhibit progressive α-synuclein aggregation in nigral dopaminergic neurons. Further, proteomic analysis of wildtype and KO synaptic fractions revealed dysregulation of oxidative stress, energy homeostasis and macroautophagy pathways, giving us insight into early pathological mechanisms.

Conclusion: Auxilin KO in mice leads to pathogenesis of Parkinsonism through dopamine dysregulation and synucleinopathy, suggesting mechanisms for PD causing auxilin mutations in humans. The occurrence of typical age-related Parkinsonian characteristics in auxilin KO mice provides compelling evidence to establish presynaptic endocytosis dysfunction as a key early pathomechanism even in sporadic PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/auxilin-knockout-mice-a-model-for-parkinsonism-with-dopamine-dysregulation-and-synucleinopathy/