Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity.
Identifieur interne : 000001 ( Main/Exploration ); précédent : 000000; suivant : 000002Endosulfine-alpha inhibits membrane-induced α-synuclein aggregation and protects against α-synuclein neurotoxicity.
Auteurs : Daniel Ysselstein [Danemark] ; Benjamin Dehay [France] ; Isabel M. Costantino [États-Unis] ; Matthew P. Frosch [États-Unis] ; Julia M. George [Royaume-Uni] ; Erwan Bezard [France] ; Jean-Christophe Rochet [Danemark] ; Georges Mccabe [États-Unis]Source :
- Acta Neuropathologica Communications [ 2051-5960 ] ; 2017-01-10.
English descriptors
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.
Url:
DOI: 10.1186/s40478-016-0403-7.
Affiliations:
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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.</div></front></TEI><affiliations><list><country><li>Danemark</li><li>France</li><li>Royaume-Uni</li><li>États-Unis</li></country></list><tree><country name="Danemark"><noRegion><name sortKey="Ysselstein, Daniel" sort="Ysselstein, Daniel" uniqKey="Ysselstein D" first="Daniel" last="Ysselstein">Daniel Ysselstein</name></noRegion><name sortKey="Rochet, Jean Christophe" sort="Rochet, Jean Christophe" uniqKey="Rochet J" first="Jean-Christophe" last="Rochet">Jean-Christophe Rochet</name></country><country name="France"><noRegion><name sortKey="Dehay, Benjamin" sort="Dehay, Benjamin" uniqKey="Dehay B" first="Benjamin" last="Dehay">Benjamin Dehay</name></noRegion><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name></country><country name="États-Unis"><noRegion><name sortKey="Costantino, Isabel M" sort="Costantino, Isabel M" uniqKey="Costantino I" first="Isabel M" last="Costantino">Isabel M. Costantino</name></noRegion><name sortKey="Frosch, Matthew P" sort="Frosch, Matthew P" uniqKey="Frosch M" first="Matthew P" last="Frosch">Matthew P. Frosch</name><name sortKey="Mccabe, Georges" sort="Mccabe, Georges" uniqKey="Mccabe G" first="Georges" last="Mccabe">Georges Mccabe</name></country><country name="Royaume-Uni"><noRegion><name sortKey="George, Julia M" sort="George, Julia M" uniqKey="George J" first="Julia M" last="George">Julia M. George</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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