Parkinson's disease (PD) is the most common neurodegenerative
movement disorder, characterized by progressive loss of dopaminergic neurons in the substantia nigra, intraneuronal deposition of misfolded
proteins known as Lewy bodies, and chronic
neuroinflammation. PD can arise from monogenic mutations, but in most cases, the etiology is unclear.
Viral infection is gaining increasing attentions as a trigger of PD. In this study, we investigated whether the PD-causative 620
aspartate (D) to
asparagine (N) mutation in the vacuolar protein sorting 35 ortholog (Vps35) precipitated herpes simplex virus (HSV)
infection. We observed that ectopic expression of Vps35 significantly reduced the proliferation and release of HSV-1 virions; the D620N mutation rendered Vps35 a partial loss of such inhibitory effects.
Tetherin is a host cell
protein capable of restricting the spread of encapsulated viruses including HSV-1 and SARS-Cov-2, both of which are implicated in the development of
parkinsonism. Compared with cells overexpressing wildtype Vps35, cells expressing mutant Vps35 with D620N had less
Tetherin on cell surfaces. Real-time and static cell imaging revealed that
Tetherin recycled through Vps35-positive endosomes. Expression of Vps35 with D620N reduced endosomal dynamics and frequency of motile
Tetherin-containing vesicles, a sign of defective production of recycling carriers. Our study suggests that the D620N mutation in Vps35 hinders
Tetherin trafficking to cell surfaces and facilitates virus spread.