Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein

Tammy Ryan, Vladimir V. Bamm, Morgan G. Stykel, Carla L. Coackley, Kayla M. Humphries, Rhiannon Jamieson-Williams, Rajesh Ambasudhan, Dick D. Mosser, Stuart A. Lipton, George Harauz and Scott D. Ryan ()
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Tammy Ryan: The University of Guelph
Vladimir V. Bamm: The University of Guelph
Morgan G. Stykel: The University of Guelph
Carla L. Coackley: The University of Guelph
Kayla M. Humphries: The University of Guelph
Rhiannon Jamieson-Williams: The University of Guelph
Rajesh Ambasudhan: Scintillon Institute
Dick D. Mosser: The University of Guelph
Stuart A. Lipton: Scintillon Institute
George Harauz: The University of Guelph
Scott D. Ryan: The University of Guelph

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03241-9

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