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 α-synuclein (α-syn) accumulation, whereas PARK9 overexpression suppresses toxicity of α-syn. However, the precise mechanism of PARK9 effect on lysosomes and α-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 α-syn into extracellular space, whereas overexpressed PARK9 promotes secretion of α-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 α-syn secretion and raise a possibility that disruption of these pathways in patients with KRS contributes to the disease pathogenesis.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Taiji
T
Tsunemi
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
Kana
K
Hamada
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 krainc@northwestern.edu.
Dimitri
D
Krainc
D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D020734:Parkinsonian Disorders / Q000235:genetics; D061251:Primary Cell Culture; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*
C514983:ATP13A2 protein, human; D056827:Endosomal Sorting Complexes Required for Transport; D051844:alpha-Synuclein; D006180:Proton-Translocating ATPases
ATP13A2; PARK9; Parkinson's disease; exosome; multivesicular body; α-synuclein