Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity.

Daniel Ysselstein, Benjamin Dehay, Isabel M. Costantino, George P. McCabe, Matthew P. Frosch, Julia M. George, Erwan Bezard, Jean-Christophe Rochet
acta neuropathol commun. 2017-01-10; 5(1):
DOI: 10.1186/s40478-016-0403-7

PubMed
Lire sur PubMed



1. Acta Neuropathol Commun. 2017 Jan 10;5(1):3. doi: 10.1186/s40478-016-0403-7.

Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects
against α-synuclein neurotoxicity.

Ysselstein D(1)(2), Dehay B(3)(4), Costantino IM(5), McCabe GP(6), Frosch MP(5),
George JM(7), Bezard E(3)(4), Rochet JC(8)(9).

Author information:
(1)Department of Medicinal Chemistry and Molecular Pharmacology, Purdue
University, West Lafayette, IN, USA.
(2)Purdue Institute for Integrative Neuroscience, Purdue University, West
Lafayette, IN, USA.
(3)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
Bordeaux, France.
(4)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(5)Department of Neurology, Massachusetts Alzheimer’s Disease Research Center,
Massachusetts General Hospital, Charlestown, MA, USA.
(6)Department of Statistics, Purdue University, West Lafayette, IN, USA.
(7)Department of Biological and Experimental Psychology, School of Biological and
Chemical Sciences, Queen Mary University of London, London, UK.
(8)Department of Medicinal Chemistry and Molecular Pharmacology, Purdue
University, West Lafayette, IN, USA. .
(9)Purdue Institute for Integrative Neuroscience, Purdue University, West
Lafayette, IN, USA. .

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.

DOI: 10.1186/s40478-016-0403-7
PMCID: PMC5223451
PMID: 28069058 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus