ATP13A2 Regulates Cellular α-Synuclein Multimerization, Membrane Association, and Externalization

Abstract

ATP13A2, a late endo-/lysosomal polyamine transporter, is implicated in a variety of neurodegenerative diseases, including Parkinson’s disease and Kufor–Rakeb syndrome, an early-onset atypical form of parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of the polyamines spermine/spermidine. Furthermore, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of α-synuclein, such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. Here, we aimed to gain more insight into how ATP13A2 is linked to α-synuclein biology in cell models with modified ATP13A2 activity. We found that loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein multimerization at the membrane, which is enhanced in conditions of oxidative stress or exposure to spermine. In contrast, overexpression of ATP13A2 wildtype (WT) had a protective effect on α-synuclein multimerization, which corresponded with reduced αsyn membrane association and stimulation of the ubiquitin-proteasome system. We also found that ATP13A2 promoted the secretion of α-synuclein through nanovesicles. Interestingly, the catalytically inactive ATP13A2 D508N mutant also affected polyubiquitination and externalization of α-synuclein multimers, suggesting a regulatory function independent of the ATPase and transport activity. In conclusion, our study demonstrates the impact of ATP13A2 on α-synuclein multimerization via polyamine transport dependent and independent functions.

The role of the endolysosomal pathway in α-synuclein pathogenesis in Parkinson’s disease

“…Adenosine triphosphate cation transporting 13A2 (ATP13A2) encodes an integral decamembrane spanning ATPase located in the lysosomal membrane that functions as a late endo-/lysosomal polyamine transporter ( van Veen et al, 2020 ). Familial ATP13A2 mutations were demonstrated to enhance α-synuclein aggregation and promote cell death ( Si et al, 2021 ). Research indicates that ATP13A2 and α-synuclein interact in the endolysosomal system and that ATP13A2 directly affects α-synuclein homeostasis ( Fonseca et al, 2015 ).…”

“…Loss of ATP13A2 impairs lysosomal membrane integrity and induces α-synuclein mutlimerisation at the ER membrane which then can further the pathology of α-synuclein ( Fonseca et al, 2015 ). Further, ATP13A2 deficiency in neuroblastoma cells leads to lysosomal dysfunction and reduces the function of the endolysosomal trafficking of α-synuclein ( Si et al, 2021 ).…”

Genetic Evidence for Endolysosomal Dysfunction in Parkinson’s Disease: A Critical Overview

“…Apoptosis dysregulation, mitochondrial dysfunction, and ER stress have emerged from animal and cellular models. Moreover, Atp13a2 LOF determines lysosomal dysfunction with defective polyamine export and autophagosome dysfunction, as effectively explored both in vivo and in vitro [ 176 , 187 , 188 , 189 , 190 , 191 ].…”

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

“…In addition, Catp-6/ ATP13A2 mutation impairs mitochondrial function in C. elegans through dysregulation of iron metabolism, and the mitochondrial dysfunction can be rescued by mitochondrial induction or iron chelation ( Anand et al, 2020 ). ATP13A2 is involved in cellular α-syn multimerization, loss of ATP13A2 induces α-syn multimerization at the lysosomal membrane through impairing membrane integrity ( Si et al, 2021 ).…”