title: Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity.
abstract: Neuropathological and genetic findings suggest that the presynaptic protein α-synuclein (aSyn) is involved in the pathogenesis of synucleinopathy disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. Evidence suggests that the self-assembly of aSyn conformers bound to phospholipid membranes in an aggregation-prone state plays a key role in aSyn neurotoxicity. Accordingly, we hypothesized that protein binding partners of lipid-associated aSyn could inhibit the formation of toxic aSyn oligomers at membrane surfaces. To address this hypothesis, we characterized the protein endosulfine-alpha (ENSA), previously shown to interact selectively with membrane-bound aSyn, in terms of its effects on the membrane-induced aggregation and neurotoxicity of two familial aSyn mutants, A30P and G51D. We found that wild-type ENSA, but not the non-aSyn-binding S109E variant, interfered with membrane-induced aSyn self-assembly, aSyn-mediated vesicle disruption and aSyn neurotoxicity. Immunoblotting analyses revealed that ENSA was down-regulated in the brains of synucleinopathy patients versus non-diseased individuals. Collectively, these results suggest that ENSA can alleviate neurotoxic effects of membrane-bound aSyn via an apparent chaperone-like activity at the membrane surface, and a decrease in ENSA expression may contribute to aSyn neuropathology in synucleinopathy disorders. More generally, our findings suggest that promoting interactions between lipid-bound, amyloidogenic proteins and their binding partners is a viable strategy to alleviate cytotoxicity in a range of protein misfolding disorders.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.|Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ysselstein
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.affiliation: Department of Neurology, Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Costantino
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, IN, USA.
authors.forename: George P
authors.initials: GP
authors.lastname: McCabe
authors.affiliation: Department of Neurology, Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Frosch
authors.affiliation: Department of Biological and Experimental Psychology, School of Biological and Chemical Sciences, Queen Mary University of London, London, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: George
authors.affiliation: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA. jrochet@purdue.edu.|Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, IN, USA. jrochet@purdue.edu.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
mesh_terms: D000256:Adenoviridae; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004926:Escherichia coli; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy* / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D053835:Unilamellar Liposomes / Q000737:chemistry; D051844:alpha-Synuclein / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D010455:Peptides; D011994:Recombinant Proteins; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; C075663:endosulfine
keywords: Endosulfine-alpha; Neurodegeneration; Parkinson’s disease; Synucleinopathy; α-Synuclein