Objective: To establish the pathogenic effects of the PD-causing VPS35 D620N mutation in vivo and address possible underlying mechanisms.

Background: D620N mutation in the vacuolar protein sorting 35 ortholog (VPS35) gene causes late-onset, autosomal dominant familial Parkinson’s disease (PD) and contributes to idiopathic PD. However, how D620N mutation leads to PD-related deficits in vivo remains unclear.

Method: To evaluate the effects of D620N mutation in vivo, we characterized VPS35 D620N knock-in (KI) mice via comprehensive assessments including behavioral, neuropathological, neurochemical, biochemical, morphological and bioenergetic analyses. We further investigated whether VPS35 D620N KI mice were more vulnerable to neurotoxin MPTP.

Results: We reported that this VPS35 D620N KI model recapitulated a spectrum of cardinal features of PD at 14 months of age which included age-dependent progressive motor deficits, significant changes in the levels of dopamine (DA) and DA metabolites in the striatum, and robust neurodegeneration of the DA neurons in the SNpc and DA terminals in the striatum, accompanied by increased neuroinflammation, and accumulation and aggregation of α-synuclein in DA neurons. Mechanistically, D620N mutation induced mitochondrial fragmentation and dysfunction in aged mice likely through enhanced VPS35-DLP1 interaction and increased turnover of mitochondrial DLP1 complexes in vivo. Finally, the VPS35 D620N KI mice displayed greater susceptibility to MPTP-mediated degeneration of nigrostriatal pathway, indicating that VPS35 D620N mutation increased vulnerability of DA neurons to environmental toxins.

Conclusion: Overall, this VPS35 D620N KI mouse model provides a powerful tool for future disease modeling and pharmacological studies of PD. Our data support the involvement of VPS35 in the development of α-synuclein pathology in vivo and revealed the important role of mitochondrial fragmentation/dysfunction in the pathogenesis of VPS35 D620N mutation-associated PD in vivo.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/vps35-d620n-knockin-mice-recapitulate-cardinal-features-of-parkinsons-disease/