Guzman Sosa, Magaly: Impact of post-translational modifications on membrane-induced alpha-synuclein aggregation in synucleinopathy disorders 

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Guzman Sosa, Magaly: Impact of post-translational modifications on membrane-induced alpha-synuclein aggregation in synucleinopathy disorders 

Submission

Title: Impact of post-translational modifications on membrane-induced alpha-synuclein aggregation in synucleinopathy disorders
Co-Authors:

Guzman Sosa, Magaly, Purdue University; Omaima Ali, Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Integrative Neuroscience, Purdue University; Sonia Donzelli, Laboratory of Chemical Biology, Neurodegeneration Brain Mind Institute, Ecole Polytechnique de Lausanne, Lausanne, Switzerland; Sayan Dutta, Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Integrative Neuroscience, Purdue University; Teshawn Johnson, Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Integrative Neuroscience, Purdue University; Ahmed Sadek, 3Laboratory of Chemical Biology, Neurodegeneration Brain Mind Institute, Ecole Polytechnique de Lausanne, Lausanne, Switzerland; Hilal A. Lashuel, 3Laboratory of Chemical Biology, Neurodegeneration Brain Mind Institute, Ecole Polytechnique de Lausanne, Lausanne, Switzerland; Jean-Christophe Rochet, Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Integrative Neuroscience, Purdue University

Abstract

Background/Significance/Rationale: Alpha-synuclein (aSYN) is a presynaptic protein that forms aggregates in the brains of individuals with Parkinson’s disease (PD) and other synucleinopathy disorders. aSYN is a natively unfolded protein in solution but can adopt an alpha-helical structure upon binding to phospholipid membranes, and this interaction is thought to play a role in vesicle trafficking and the release of neurotransmitters. Data from our group and others suggest that the aggregation of membrane-bound aSYN plays a central role in the protein’s neurotoxicity in PD via a mechanism involving vesicle disruption. Furthermore, increasing evidence suggests that the mechanism of membrane-induced aggregation is distinct from the more extensively studied process of aSYN aggregation in the absence of membranes. Although various post-translational modifications (PTMs) of aSYN identified in cell culture, animal models, or human brain have been shown to modulate aSYN aggregation in the absence of lipids, little is known about the effects of PTMs on membrane-induced aSYN self-assembly. We hypothesize that certain PTMs promote the protein’s aggregation at the surface of phospholipid membranes, resulting in enhanced aSYN neurotoxicity, based on evidence that some PTMs alter the conformation of membrane-bound aSYN and/or perturb aSYN-membrane interactions.

Methods: Recombinant aSYN variants with N- and C-terminal truncations previously identified in the human brain were characterized in terms of their relative propensities to undergo membrane-induced self-assembly. We also characterized our panel of truncated aSYN variants in terms of their ability to induce pathology when expressed from adenoviral vectors in rat primary neuronal cultures.

Results/Findings: We found that aSYN variants with N- or C-terminal truncations underwent more extensive oligomerization and accelerated fibrillization (yielding fibrils with altered morphologies visualized by EM) compared to WT aSYN when incubated with phospholipid vesicles at a low pH mimicking the acidic conditions of endocytic compartments. Our results from studies of primary neuronal cells cultures showed that the truncated variant aSyn1-124 had an increased ability to induce the fibrillization of endogenous aSyn in cultured neurons via a seeding mechanism.

Conclusions/Discussion: The results of these studies provide new insights into the role of aSYN PTMs and membrane-induced aggregation in the pathology of synucleinopathy disorders.

Translational/Human Health Impact: Our findings set the stage for developing therapies targeting aSYN PTM variants in the brains of patients.

Video

Slides

|2022-08-31T17:25:50-04:00August 23rd, 2022|2022 Annual Meeting Presentations|Comments Off on Guzman Sosa, Magaly: Impact of post-translational modifications on membrane-induced alpha-synuclein aggregation in synucleinopathy disorders 

About the Author:

James Dudley

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