ATP13A2/PARK9 Regulates Secretion of Exosomes and α-Synuclein

Kufor-Rakeb syndrome (KRS) is caused by loss-of-function mutations in ATP13A2 (PARK9) and characterized by juvenile-onset parkinsonism, pyramidal signs, and cognitive decline. Previous studies suggested that PARK9 deficiency causes lysosomal dysfunction and alpha-synuclein (alpha-syn) accumulation, whereas PARK9 overexpression suppresses toxicity of alpha-syn. However, the precise mechanism of PARK9 effect on lysosomes and alpha-syn has been unknown. Here, we found that overexpressed PARK9 localized to multivesicular bodies (MVBs) in the human H4 cell line. The results from patient fibroblasts showed that loss of PARK9 function leads to decreased number of the intraluminal vesicles in MVBs and diminished release of exosomes into culture media. By contrast, overexpression of PARK9 results in increased release of exosomes in H4 cells and mouse primary cortical neurons. Moreover, loss of PARK9 function resulted in decreased secretion of alpha-syn into extracellular space, whereas overexpressed PARK9 promotes secretion of alpha-syn, at least in part via exosomes. Finally, we found that PARK9 regulates exosome biogenesis through functional interaction with the endosomal sorting complex required for transport machinery. Together, these data suggest the involvement of PARK9 in the biogenesis of exosomes and alpha-syn secretion and raise a possibility that disruption of these pathways in patients with KRS contributes to the disease pathogenesis.