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Endothelin‐converting enzymes degrade α‐synuclein and are reduced in dementia with Lewy bodies
Author(s) -
Miners James Scott,
Love Seth
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13974
Subject(s) - dementia with lewy bodies , lewy body , pathogenesis , medicine , endothelin receptor , endocrinology , endothelin 1 , chemistry , biology , microbiology and biotechnology , pathology , parkinson's disease , receptor , dementia , disease
We have examined the roles of the endothelin‐converting enzyme‐1 and ‐2 ( ECE ‐1 and ECE ‐2) in the homeostasis of α‐synuclein (α‐syn) and pathogenesis of Lewy body disease. The ECE s are named for their ability to convert inactive big endothelin to the vasoactive peptide endothelin‐1 ( EDN 1). We have found that ECE ‐1 and ECE ‐2 cleave and degrade α‐syn in vitro and si RNA ‐mediated knockdown of ECE ‐1 and ECE ‐2 in SH ‐ SY 5Y neuroblastoma cells significantly increased α‐syn both intracellularly (within the cell lysate) ( p < 0.05 for both ECE ‐1 and ‐2) and extracellularly (in the surrounding medium) ( p < 0.05 for ECE ‐1 and p = 0.07 for ECE ‐2). Double immunofluorescent labelling showed co‐localization of ECE ‐1 and ECE ‐2 with α‐syn within the endolysosomal system (confirmed by a proximity ligation assay). To assess the possible relevance of these findings to human Lewy body disease, we measured ECE ‐1 and ECE ‐2 levels by sandwich ELISA in post‐mortem samples of cingulate cortex (a region with a predilection for Lewy body pathology) in dementia with Lewy bodies ( DLB ) and age‐matched controls. ECE ‐1 ( p < 0.001) and ECE ‐2 ( p < 0.01) levels were significantly reduced in DLB and both enzymes correlated inversely with the severity of Lewy body pathology as indicated by the level of α‐syn phosphorylated at Ser129 ( r = −0.54, p < 0.01 for ECE ‐1 and r = −0.49, p < 0.05 for ECE ‐2). Our novel findings suggest a role for ECE s in the metabolism of α‐syn that could contribute to the development and progression of DLB .