Mutations in VPS35 that are associated with Parkinson's disease increase the interaction of VPS35 with mitochondrial DLP1, leading to removal of the DLP1 complexes and mitochondrial fragmentation. Structural and functional mitochondrial impairments caused by mutant VPS35 are observed in vitro using cultured neurons and fibroblasts from individuals with PD and in vivo in mouse substantia nigra neurons, where they induce neurodegeneration. Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein–recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35D620N mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle–dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.

Significance: Endoplasmic reticulum (ER) and mitochondria form close associations that serve as a critical signaling platform. Loss-of-function mutations in DJ-1 are associated with autosomal recessive early onset Parkinson’s disease (PD). We found that DJ-1 knockout caused significant impairments in the structure and function of ER-mitochondria association in neuronal cells and in vivo. Reduced DJ-1 was associated with deficits in ER-mitochondria association in the substantia nigra of sporadic PD. Our study identifies DJ-1 as a critical component of the macrocomplex containing IP3R3-Grp75-VDAC1 at mitochondria-associated membrane and as playing an important role in the regulation of the integrity and function of ER-mitochondria association. Our research offers insights into the regulation mechanism of ER-mitochondria association and the pathogenic mechanism of DJ-1 deficiency in PD.

The number and health burden of Parkinson’s disease increase rapidly in China. It is estimated that China will have nearly half of the Parkinson’s disease population in the world in 2030. In this review, we present an overview of epidemiology and health economics status of Parkinson’s disease across China and discuss the risk factors of Parkinson’s disease and related complications. From the view of clinical research, we also discuss the current status of clinical trials, diagnostic biomarkers, treatment of Parkinson’s disease, tertiary network and post-occupation education in Chinese Parkinson’s disease clinics.

α-Synuclein misfolding and aggregation play an important role in the pathogenesis of Parkinson’s disease (PD). Loss of function and mutation of the PARK7/DJ-1 gene cause early-onset familial PD. DJ-1 can inhibit α-synuclein aggregation, and may function at an early step in the aggregation process. Soluble wild-type α-synuclein is mainly degraded by chaperone-mediated autophagy (CMA), and impairment of CMA is closely related to the pathogenesis of PD. Here, we investigated whether DJ-1 could reduce α-synuclein accumulation and aggregation by CMA. DJ-1 knockout mice and DJ-1 siRNA knockdown SH-SY5Y cells were used to investigate the potential mechanisms underlying the relationship between DJ-1 deficiency and α-synuclein aggregation. First, we confirmed that DJ-1 deficiency increased the accumulation and aggregation of α-synuclein in both SH-SY5Y cells and PD animal models, and overexpression of DJ-1 in vitro effectively decreased α-synuclein levels. α-Synuclein overexpression activated CMA by elevating the levels of lysosome-associated membrane protein type-2A (LAMP2A), but DJ-1 deficiency suppressed upregulation of LAMP2A. DJ-1 deficiency downregulated the level of lysosomal 70 kDa heat-shock cognate protein but not the levels of that in homogenates. Further studies showed that DJ-1 deficiency accelerated the degradation of LAMP2A in lysosomes, leading to the aggregation of α-synuclein. Our study suggests that DJ-1 deficiency aggravates α-synuclein aggregation by inhibiting the activation of CMA and provides further evidence of the molecular interaction between PD-related proteins via the CMA pathway.