Investigating the relationship between alpha-synuclein and mitochondrial quality control

Thorne, Naomi Jasmin (2022) Investigating the relationship between alpha-synuclein and mitochondrial quality control. Quality Control in Life Processes, Goethe University, Frankfurt, Germany. 04 - 07 Oct 2022.

Record type: Conference or Workshop Item (Poster)

Abstract

Mitochondrial quality control (mito-QC) co-ordinates dynamics changes in the mitochondrial network to maintain cellular health. Dysregulation in mito-QC has been associated with numerous pathologies, including Parkinson’s disease (PD) which is characterised by degeneration of dopaminergic neurons in the substantia nigra. The mechanism for neuronal death in PD is still not known, but it has been linked to aggregation of alpha-synuclein; a protein which pathologically forms Lewy-body inclusions. A relationship between alpha-synuclein and mito-QC has been established based on the presence of dysfunctional mitochondria in both PD patients and models of alpha-synuclein pathology. Since alpha-synuclein associates with and remodels phospholipid membranes, has a mitochondrial targeting sequence and can enter mitochondria through the TOM complex, it may have a close relationship with mitochondria in both a physiological and pathological context. Recent research has shown that monomeric alpha-synuclein may use mitochondrial membranes to seed aggregation of toxic oligomeric species, potentiating disease pathogenesis. Despite this, research often uses pre-formed fibrillar alpha-synuclein to assess pathogenic phenotypes, short-cutting the important oligomerisation process that has been hypothesised to cause more damage than the resultant fibrils. As such, we applied CRISPR/Cas9 technology to create two stable alpha-synuclein overexpression cell lines in SH-SY5Y, providing an environment that permits de-novo oligomer formation. We evaluated whether gain-of-function influenced mito-QC through analysing responses to mitochondrial damage in cells overexpressing either wild-type or A53T alpha-synuclein, the latter being a PD-associated mutant with an increased aggregation propensity. This included investigating mitochondrial-derived vesicle formation, PINK1/Parkin mitophagy and alterations in the mitochondrial network alongside probing for direct associations between alpha-synuclein and mitochondria. Our results provide a thorough assessment of the relationship between alpha-synuclein, mitochondria and the endolysosomal system in a pathological context. We hypothesise that alpha-synuclein is able to negatively influence protective mito-QC mechanisms in a pathological context.

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