Abstract
Neuronal loss in Parkinson’s disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface. Whereas exposed cardiolipin specifically binds to and facilitates refolding of α-syn fibrils, prolonged cardiolipin exposure in SNCA-mutants initiates recruitment of LC3 to the mitochondria and mitophagy. Moreover, we find that co-culture of SNCA-mutant neurons with their isogenic controls results in transmission of α-syn pathology coincident with mitochondrial pathology in control neurons. Transmission of pathology is effectively blocked using an anti-α-syn monoclonal antibody (mAb), consistent with cell-to-cell seeding of α-syn.
Highlights
Neuronal loss in Parkinson’s disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis
We show that outer mitochondrial membrane (OMM)-localized cardiolipin can pull α-syn monomers away from oligomeric fibrils and facilitate their refolding from aggregated β-sheet forms back to monomers comprising α-helices, effectively buffering synucleinopathy
Using either human isogenic induced pluripotent stem cell (hiPSC)-derived clones that allow for comparison of the A53T-SNCA mutation (A53T) with isogenic-corrected controls (Corr)[12,16] or hESCderived clones that allow for comparison of wild type (WT)-SNCA with A53T-SNCA or E46K-SNCA mutations, we characterized the lineage progression of human pluripotent stem cells (hPSCs) to DA neurons
Summary
Neuronal loss in Parkinson’s disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Mutation of the SNCA gene is causal in several rare familial forms of PD, mutations in the SNCA locus are consistently identified in genome-wide association studies of sporadic PD11, and α-syn protein is commonly found in Lewy neurites of idiopathic disease cases These findings emphasize the need to understand how altered α-syn structure and function relate to PD pathogenesis in general terms. The generation of human isogenic induced pluripotent stem cell (hiPSC) and embryonic stem cell (hESC) models of familial PD has facilitated the analysis of PD pathology at the cellular level[16], allowing us to contrast A9-type DA neurons (hNs) harboring the SNCA-A53T mutation with isogenic, mutationcorrected controls[12] Using these systems, we describe a novel mechanism in which the mitochondrial membrane lipid cardiolipin plays a vital role in the folding of α-syn protein. Using hPSC-derived A9-type DA neurons, this work represents the first demonstration of direct cell-to-cell transmission of endogenous, mutant α-syn from diseased human neurons to non-diseased human neurons, and identifies cardiolipin exposure on mitochondrial membranes as a key signal in PD pathogenesis
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