Phenotypic spectrum of alpha-synuclein mutations: New insights from patients and cellular models.
The identification of the p.A53T mutation in the SNCA gene encoding alpha-synuclein (alpha-syn), as causative of autosomal dominant Parkinson disease (PD) represented a fundamental milestone, which paved the way to the extremely prolific field of PD genetics. Despite being the oldest player in this field and only a rare cause of inherited PD, research on alpha-syn has remained incredibly active over nearly twenty decades, leading to identify alpha-syn aggregation as a key mechanism in PD pathogenesis. The past two years have witnessed new exciting findings, with the discovery of at least three novel pathogenic mutations (p.H50Q, p.G51D and p.A53E) causative of complex parkinsonian phenotypes, and the identification of additional patients carrying "old" SNCA mutations (p.A53T, p.A30P, p.E46K and whole gene multiplications), which has allowed to further expand their phenotypic spectrum. This review aims at providing a clinical and functional update on the most recent findings in alpha-syn genetics, at the same time discussing novel avenues of SNCA research such as those on somatic mutations and epigenetic mechanisms.
CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Department of Neurology and Psychiatry, "Sapienza" University of Rome, Rome, Italy.
Simona
S
Petrucci
CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Monia
M
Ginevrino
CSS-Mendel Institute, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Section of Neurosciences, Department of Medicine and Surgery, University of Salerno, Salerno, Italy. Electronic address: e.valente@css-mendel.it.
Enza Maria
EM
Valente
D000818:Animals; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D051844:alpha-Synuclein / Q000235:genetics*
C497604:SNCA protein, human; D051844:alpha-Synuclein
Alpha-synuclein; Genotype-phenotype correlates; Mutations; SNCA