Objective: In this study, we investigated the morphology of mitochondria and localization of alpha-synuclein as driven by alpha-synuclein isolated from PD and MSA brain-derived tissue.

Background: Parkinson’s disease (PD) and multiple system atrophy (MSA) are neurodegenerative movement disorders with the hallmark feature of pathologic aggregation of α-syn. There are known bioenergetic deficits in PD with known Complex I inhibition in mitochondria in the brain. MSA has also been associated with CoQ2 mutations with resultant alteration in CoQ10 biosynthesis and electron transport chain dysfunction.

Method: PD, MSA, and control (non-synucleinopathy) brain tissue was obtained from Washington University St Louis Movement Disorder brain bank. a-Syn overexpressing HEK293 cells were plated at 260,000 cells per well in a 12 well-plate and exposed to insoluble brain fractions after a 3min 65A sonication on ice (QSonica) and incubated for inclusion formation for 72 hours. Cells were then fixed in glutaraldehyde for 5min. Tissue was embedded in Epon Epoxy resin and sectioned and mounted on formar grids. Sections were stained with uranyl acetate and imaged on a Talos FEI F200X transmission electron microscope.

Results: Cells exposed to PD insoluble brain fractions uniformly demonstrated a severe and prominent deformation of the mitochondria. Mitochondria were increased in size with a ballooned appearance and demonstrated a perturbation of the cristae. Increased distance between cristae contributed to a decrease in the cristae density. In MSA-exposed cells, mitochondrial structure was much less affected, but there were striking differences. A subpopulation of mitochondria were greatly elongated in comparison to control tissue-exposed mitochondria.

Conclusion: These results demonstrate a prominent change in mitochondrial morphology in cells exposed to PD brain tissue vs those exposed to MSA brain tissue in this in vitro cell system. These findings are in line with a prominent role for mitochondrial toxicity in PD. Intriguingly, mitochondrial appearance in MSA brain tissue exposed cells was much less affected and elongated structures seen may suggest a deficiency in mitochondrial fusion/fission. These structural studies argue for different mitochondrial effects in PD and MSA. Further studies are warranted to confirm potential pathophysiologic mechanisms.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/differential-effect-of-alpha-synuclein-on-mitochondrial-morphology-in-pd-and-msa/