VPS35 and the mitochondria: Connecting the dots in Parkinson's disease pathophysiology

Mutations in VPS35 (PARK17), a key molecule in the retromer complex, are a rare cause of autosomal dominant Parkinson's disease (PD), the second most common neurodegenerative disorder. VPS35 exerts crucial functions within the cell in terms of regulating endosomal trafficking. However new data suggest its relevance also in the regulation of mitochondrial dynamics and homeostasis. Herein, we review the crosstalk between VPS35 and the mitochondria, highlighting the potential relevance to PD pathogenesis. VPS35 is not only a critical player in pathways connected to α-synuclein accumulation and clearance, but also plays a key role in ensuring mitochondrial stability and function. The genetic links of VPS35 to PD and the involvement of VPS35 in different PD related pathological mechanisms highlight the potential for targeting VPS35 as a neuroprotective strategy for PD.