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The H50Q mutation enhances ?-synuclein aggregation, secretion and toxicity.
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J Biol Chem 2014 Jun;
Authors: Ossama Khalaf, Bruno Fauvet, Abid Oueslati, Igor Dikiy, Anne-Laure Mahul-Mellier, Francesco Simone Ruggeri, Martial Mbefo, Filip Vercruysse, Giovanni Dietler, Seung-Jae Lee, David Eliezer, Hilal A Lashuel
Over the last two decades, the identification of missense mutations in the ?-synuclein (?-Syn) gene SNCA in families with inherited Parkinson's disease (PD) has reinforced the central role of ?-Syn in PD pathogenesis. Recently, a new missense mutation (H50Q) in ?-Syn was described in patients with a familial form of PD and dementia. Here we investigated the effects of this novel mutation on the biophysical properties of ?-Syn and the consequences for its cellular function. We found that the H50Q mutation affected neither the structure of free or membrane-bound ?-Syn monomer nor its interaction with metals or its capacity to be phosphorylated in vitro. However, compared to the wild-type protein, the H50Q mutation accelerated ?-Syn fibrillization in vitro. In cell-based models, H50Q mutation did not affect neither ?-Syn subcellular localization, nor its ability to be phosphorylated by PLK2 and GRK6. Interestingly, H50Q increased ?-Syn secretion from SHSY5Y cells into culture medium and induced more mitochondrial fragmentation in hippocampal neurons. Toxicity analysis revealed that, while the transient overexpression of WT or H50Q did not induce toxicity, both species induced significant cell death when added to the culture medium of hippocampal neurons. Strikingly, H50Q exhibited more toxicity, suggesting that the H50Q-related enhancement of ?-Syn aggregation and secretion may play a role in the extracellular toxicity of this mutant. Together, our results provide novel insight into the mechanism by which this newly described PD-associated mutation may contribute to the pathogenesis of PD and related disorders.
PMID: 24936070 [PubMed - as supplied by publisher]