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Upregulation of Cellular Palmitoylation Mitigates α‐Synuclein Accumulation and Neurotoxicity
ABSTRACT Background Synucleinopathies, including Parkinson's disease (PD), are characterized by α‐synuclein (αS) cytoplasmic inclusions. αS‐dependent vesicle‐trafficking defects are important in PD pathogenesis, but their mechanisms are not well understood. Protein palmitoylation, post‐translat...
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Published in: | Movement disorders 2021-02, Vol.36 (2), p.348-359 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | ABSTRACT
Background
Synucleinopathies, including Parkinson's disease (PD), are characterized by α‐synuclein (αS) cytoplasmic inclusions. αS‐dependent vesicle‐trafficking defects are important in PD pathogenesis, but their mechanisms are not well understood. Protein palmitoylation, post‐translational addition of the fatty acid palmitate to cysteines, promotes trafficking by anchoring specific proteins to the vesicle membrane. αS itself cannot be palmitoylated as it lacks cysteines, but it binds to membranes, where palmitoylation occurs, via an amphipathic helix. We hypothesized that abnormal αS membrane‐binding impairs trafficking by disrupting palmitoylation. Accordingly, we investigated the therapeutic potential of increasing cellular palmitoylation.
Objectives
We asked whether upregulating palmitoylation by inhibiting the depalmitoylase acyl‐protein‐thioesterase‐1 (APT1) ameliorates pathologic αS‐mediated cellular phenotypes and sought to identify the mechanism.
Methods
Using human neuroblastoma cells, rat neurons, and iPSC‐derived PD patient neurons, we examined the effects of pharmacologic and genetic downregulation of APT1 on αS‐associated phenotypes.
Results
APT1 inhibition or knockdown decreased αS cytoplasmic inclusions, reduced αS serine‐129 phosphorylation (a PD neuropathological marker), and protected against αS‐dependent neurotoxicity. We identified the APT1 substrate microtubule‐associated‐protein‐6 (MAP6), which binds to vesicles in a palmitoylation‐dependent manner, as a key mediator of these effects. Mechanistically, we found that pathologic αS accelerated palmitate turnover on MAP6, suggesting that APT1 inhibition corrects a pathological αS‐dependent palmitoylation deficit. We confirmed the disease relevance of this mechanism by demonstrating decreased MAP6 palmitoylation in neurons from αS gene triplication patients.
Conclusions
Our findings demonstrate a novel link between the fundamental process of palmitoylation and αS pathophysiology. Upregulating palmitoylation represents an unexplored therapeutic strategy for synucleinopathies. © 2020 International Parkinson and Movement Disorder Society |
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ISSN: | 0885-3185 1531-8257 |
DOI: | 10.1002/mds.28346 |