Endothelin-converting enzymes degrade α-synuclein and are reduced in dementia with Lewy bodies.
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 ECEs are named for their ability to convert inactive big endothelin to the vasoactive peptide endothelin-1 (EDN1). We have found that ECE-1 and ECE-2 cleave and degrade α-syn in vitro and siRNA-mediated knockdown of ECE-1 and ECE-2 in SH-SY5Y 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 ECEs in the metabolism of α-syn that could contribute to the development and progression of DLB.
Dementia Research Group, University of Bristol, Bristol, UK.
James Scott
JS
Miners
Dementia Research Group, University of Bristol, Bristol, UK.
Seth
S
Love
D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D000072396:Endothelin-Converting Enzymes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein; C000606923:ECE1 protein, human; C000606924:ECE2 protein, human; D000072396:Endothelin-Converting Enzymes
ECE-1; ECE-2; dementia with Lewy bodies; endothelin-converting enzyme; α-synuclein