Cardiolipin exposure on the outer mitochondrial membrane modulates α‐synuclein proteostasis in hPSC‐derived Parkinson's Disease neurons
Authors: Ryan Scott D. , Ryan Tammy L. , Bamm Vladamir V. , Stykel Morgan G. , Coackley Carla C. , Humphries Kayla , Harauz George 
Published: June 2021

Introduction

The decline of voluntary motor function in Parkinson's disease (PD) is caused by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta. The death of these neurons is preceded by the formation of intracellular proteinaceous aggregates known as Lewy Bodies, which contain a variety of misfolded protein components, including α‐synuclein (α‐syn). Although SNCA mutations (α‐syn gene) are causal in several rare familial forms of PD, mutations in the SNCA locus are also consistently identified in genome‐wide association studies (GWAS) of sporadic PD, 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.

Approach

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, allowing us to contrast A9‐type DA neurons (hNs) harboring the SNCA‐A53T or SNCA‐E46K mutations with isogenic, mutation‐corrected controls. Using these systems in combination with SNCA‐A53T transgenic animals, we describe a novel mechanism in which the mitochondrial membrane lipid cardiolipin plays a vital role in preventing accumulation of α‐syn protein aggregates. This protective process is disrupted by both SNCA‐A53T and SNCA‐E46K mutations.

Results

Here, we demonstrate that cardiolipin translocates to the outer mitochondrial membrane (OMM) in both A53T and E46K SNCA‐mutant hNs at the onset of α‐syn deposition, where it binds α‐syn, facilitating the folding of intrinsically disordered α‐syn to an a‐helical conformation. This finding was confirmed in SNCA‐A53T transgenic mouse brains. Furthermore, we show that OMM‐localized cardiolipin can pull α‐syn monomers away from multimeric‐fibrils and facilitate their re‐folding, from multimeric b‐sheet forms back to monomers comprising a‐helices, effectively buffering α‐syn pathology. Surprisingly, both the A53T and E46K α‐syn mutations reduced the kinetic rate of cardiolipin‐mediated α‐syn re‐folding relative to wild‐type (WT), increasing the level of α‐syn present at the OMM in A53T and E46K hNs. Binding of A53T and E46K α‐syn to cardiolipin led to significantly increased LC3 recruitment to the OMM relative to WT α‐syn, which in turn increased mitochondrial stress, triggering excessive mitophagy.

Significance

This work represents the first demonstration of α‐syn as a modulator of LC3 function, and identifies cardiolipin exposure on mitochondrial membranes as a key regulator of PD pathogenesis.

Support or Funding Information

This work was supported in part by the Parkinson Society of Canada (2014‐685 to SDR), the Natural Sciences and Engineering Research Council of Canada (RG060805 to SDR, RG121541 to GH), the CRC Program (GH).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.