title: The H50Q mutation enhances α-synuclein aggregation, secretion, and toxicity.
abstract: Over the last two decades, the identification of missense mutations in the α-synuclein (α-Syn) gene SNCA in families with inherited Parkinson disease (PD) has reinforced the central role of α-Syn in PD pathogenesis. Recently, a new missense mutation (H50Q) in α-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 α-Syn and the consequences for its cellular function. We found that the H50Q mutation affected neither the structure of free or membrane-bound α-Syn monomer, its interaction with metals, nor its capacity to be phosphorylated in vitro. However, compared with the wild-type (WT) protein, the H50Q mutation accelerated α-Syn fibrillization in vitro. In cell-based models, H50Q mutation did not affect α-Syn subcellular localization or its ability to be phosphorylated by PLK2 and GRK6. Interestingly, H50Q increased α-Syn secretion from SHSY5Y cells into culture medium and induced more mitochondrial fragmentation in hippocampal neurons. Although 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 α-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.
authors.affiliation: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and.
authors.forename: Ossama
authors.initials: O
authors.lastname: Khalaf
authors.affiliation: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fauvet
authors.affiliation: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and.
authors.forename: Abid
authors.initials: A
authors.lastname: Oueslati
authors.affiliation: Department of Biochemistry, Program in Structural Biology, Weill Cornell Medical College, New York, New York 10065, and.
authors.forename: Igor
authors.initials: I
authors.lastname: Dikiy
authors.affiliation: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Mahul-Mellier
authors.affiliation: Laboratory of Physics of Living Matter, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Francesco Simone
authors.initials: FS
authors.lastname: Ruggeri
authors.affiliation: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and.
authors.forename: Martial K
authors.initials: MK
authors.lastname: Mbefo
authors.affiliation: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and.
authors.forename: Filip
authors.initials: F
authors.lastname: Vercruysse
authors.affiliation: Laboratory of Physics of Living Matter, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Dietler
authors.affiliation: Department of Biomedical Science and Technology, Konkuk University, Seoul 143-701, South Korea.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Program in Structural Biology, Weill Cornell Medical College, New York, New York 10065, and.
authors.forename: David
authors.initials: D
authors.lastname: Eliezer
authors.affiliation: From the Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute and hilal.lashuel@epfl.ch.
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D050356:Lipid Metabolism; D008670:Metals / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D010766:Phosphorylation; D066329:Protein Aggregates / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology
chemical_list: D008670:Metals; D050505:Mutant Proteins; D066329:Protein Aggregates; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Amyloid; Membrane; Metal Ion-Protein Interaction; Mitochondria; Mitochondrial Dysfunction; Mutation; Protein Aggregation; α-Synuclein