“Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of alpha-synuclein.” Rutherford NJ, Moore BD, Golde TE, Giasson BI. J Neurochem 2014.
http://www.ncbi.nlm.nih.gov/pubmed/24984882?dopt=Citation
Abstract
The discoveries of mutations in SNCA were seminal findings that resulted in the knowledge that α-synuclein is the major component of Parkinson’s disease-associated Lewy bodies. Since the pathologic roles of these protein inclusions and SNCA mutations are not completely established, we characterized the aggregation properties of the recently identified SNCA mutations, H50Q and G51D, to provide novel insights. The properties of recombinant H50Q, G51D and wild-type α-synuclein to polymerize and aggregate into amyloid were studied using K114 fluorometry, sedimentation analyses, electron microscopy and atomic force microscopy. These studies showed that the H50Q mutation increases the rate of α-synuclein aggregation while the G51D mutation has the opposite effect. However, H50Q and G51D α-synuclein could still be similarly induced to form intracellular aggregates from the exposure to exogenous amyloidogenic seeds under conditions that promote their cellular entry. Both mutant α-synuclein proteins, but especially G51D, promoted cellular toxicity under cellular stress conditions. These findings reveal that the novel pathogenic SNCA mutations, H50Q and G51D, have divergent effects on aggregation properties relative to the wild type protein, with G51D α-synuclein demonstrating reduced aggregation despite presenting with earlier disease, suggesting that these mutants promote different mechanisms of α-synuclein pathogenesis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
KEYWORDS:
Parkinson’s disease; SNCA mutation; protein aggregation; α-synuclein