Journal
DISEASE MODELS & MECHANISMS
Volume 13, Issue 1, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.040899
Keywords
alpha-Synuclein; Synucleinopathy; Parkinson's disease; Mitochondria; Cardiolipin; PMCA
Categories
Funding
- National Health and Medical Research Council [APP1041413, APP1132604]
- Carol Willesee PhD Scholarship at the University of Melbourne
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The misfolding and aggregation of the largely disordered protein, alpha-synudein, is a central pathogenic event that occurs in the synucleinopathies, a group of neurodegenerative disorders that includes Parkinson's disease. While there is a clear link between protein misfolding and neuronal vulnerability, the precise pathogenic mechanisms employed by disease-associated alpha-synuclein are unresolved. Here, we studied the pathogenicity of misfolded alpha-synuclein produced using the protein misfolding cyclic amplification (PMCA) assay. To do this, previous published methods were adapted to allow PMCA-induced protein fibrillization to occur under non-toxic conditions. Insight into potential intracellular targets of misfolded alpha-synuclein was obtained using an unbiased lipid screen of 15 biologically relevant lipids that identified cardiolipin (CA) as a potential binding partner for PMCA-generated misfolded alpha-synuclein. To investigate whether such an interaction can impact the properties of alpha-synuclein misfolding, protein fibrillization was carried out in the presence of the lipid. We show that CA both accelerates the rate of alpha-synuclein fibrillization and produces species that harbourenhanced resistance to proteolysis. Because CA is virtually exclusively expressed in the inner mitochondrial membrane, we then assessed the ability of these misfolded species to alter mitochondrial respiration in live non-transgenic SH-SY5Y neuroblastoma cells. Extensive analysis revealed that misfolded alpha-synudein causes hyperactive mitochondrial respiration without causing any functional deficit. These data give strong supportfor the mitochondrion as a target for misfolded alpha-synuclein and reveal persistent, hyperactive respiration as a potential upstream pathogenic event associated with the synucleinopathies. This article has an associated First Person interview with the first author of the paper.
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