ATP13A2/PARK9 Regulates Secretion of Exosomes and α-Synuclein

Abstract

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 ␣-synuclein (␣-syn) accumulation, whereas PARK9 overexpression suppresses toxicity of ␣-syn. However, the precise mechanism of PARK9 effect on lysosomes and ␣-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 ␣-syn into extracellular space, whereas overexpressed PARK9 promotes secretion of ␣-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 ␣-syn secretion and raise a possibility that disruption of these pathways in patients with KRS contributes to the disease pathogenesis.

New insights into cellular α-synuclein homeostasis in health and disease

“…In terms of pathology, the proposed new pathway (Figure 1) of depolymerization of native aSyn multimers leading to the hallmark of synucleinopathies, large aSyn aggregates, will need to be further substantiated, most importantly in animal models. With cellular aSyn dyshomeostasis in PD probably being upstream of other pathological changes, the new insights reviewed here will have to be connected to other emerging themes in the field, such as the interplay between aSyn and the E3 ligase Nedd4 [69][70][71][72] and the hypothesis of cell-to-cell spreading of the protein being important in the pathogenesis of synucleinopathies [73][74][75], suggesting a potential role for aSyn release from neurons [76][77][78].…”

Exosomes in the Pathology of Neurodegenerative Diseases

“…Through a process involving ceramide, tetraspanins, or endosomal sorting complexes required for transport (ESCRT) components, ␣-synuclein is directed into MVBs. Both PARK9 (51,52) and Rab11 (48) have been shown to promote the exosomal release of ␣-synuclein. C, APP is a cell surface transmembrane protein that can be processed by a number of proteases.…”

“…PARK9 has also been found to regulate extracellular ␣-synuclein (50). PARK9 deficiency causes lysosomal dysfunction and ␣-synuclein accumulation, whereas PARK9 overexpression suppresses cellular toxicity of ␣-synuclein (51,52). Importantly, PARK9 is also involved in the biogenesis of exosomes and has been found to increase exosomal ␣-synuclein (51, 52).…”

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

“…On the other hand, αSYN oligomers in the lysosome may impact on GBA, leading to its malfunction and creating a vicious cycle of lysosomal failure and pathological αSYN accumulation (Mazzulli et al 2011). Another piece of evidence showed that mutations in the ATP13A2 gene, which encodes a lysosomal ATPase cation transporter and causes autosomal recessive familial PD (PARK9, also known as Kufor-Rakeb syndrome), enhances αSYN aggregation and affects its exosomal secretion into the extracellular space (Tsunemi et al 2014;Lopes da Fonseca et al 2016). Taken together, these genetic discoveries strongly support the notion that the defects in endo-lysosomal trafficking/functions are illuminated as convergent mechanisms for PD and related neurological disorders.…”