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Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of ?-synuclein.
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J Neurochem 2014 Jul;
Authors: Nicola J Rutherford, Brenda D Moore, Todd E Golde, Benoit I Giasson
The discoveries of mutations in SNCA were seminal findings that resulted in the knowledge that ?-synuclein (?S) 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 ?S to polymerize and aggregate into amyloid were studied using (trans,trans)-1-bromo-2,5-bis-(4-hydroxy)styrylbenzene fluorometry, sedimentation analyses, electron microscopy, and atomic force microscopy. These studies showed that the H50Q mutation increases the rate of ?S aggregation, whereas the G51D mutation has the opposite effect. However, H50Q and G51D ?S 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 ?S 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 ?S demonstrating reduced aggregation despite presenting with earlier disease onset, suggesting that these mutants promote different mechanisms of ?S pathogenesis. The ?-synuclein (SNCA) mutations, H50Q and G51D, cause Parkinson's disease. We found that H50Q increases and G51D decreases the rate of ?-synuclein aggregation in vitro, and cells over-expressing the mutant proteins show decreased viability when stressed, compared to wild type. G51D is the first SNCA mutation to show decreased ?-synuclein aggregation, suggesting a distinct disease mechanism to other SNCA mutations.
PMID: 24984882 [PubMed - as supplied by publisher]