title: Involvement of Gaucher Disease Mutations in Parkinson Disease.
abstract: Gaucher disease is an autosomal recessive lysosomal storage disorder, caused by mutations in the GBA gene. The frequency of Gaucher disease patients and heterozygote carriers that developed Parkinson disease has been found to be above that of the control population. This fact suggests that mutations in the GBA gene can be involved in Parkison's etiology. Analysis of large cohorts of patients with Parkinson disease has shown that there are significantly more cases bearing GBA mutations than those found among healthy individuals. Functional studies have proven an interaction between α-synuclein and GBA, the levels of which presented an inverse correlation. Mutant GBA proteins cause increases in α-synuclein levels, while an inhibition of GBA by α-synuclein has been also demonstrated. Saposin C, a coactivator of GBA, has been shown to protect GBA from this inhibition. Among the GBA variants associated with Parkinson disease, E326K seems to be one of the most prevalent. Interestingly, it is involved in Gaucher disease only when it forms part of a double-mutant allele, usually with the L444P mutation. Structural analyses have revealed that both residues (E326 and L444) interact with Saposin C and, probably, also with α-synuclein. This could explain the antagonistic role of these two proteins in relation to GBA.
authors.affiliation: Department of Genetics, Faculty of Biology, Universitat de Barcelona, IBUB, CIBERER, Barcelona, Spain.
authors.forename: Lluisa
authors.initials: L
authors.lastname: Vilageliu
authors.affiliation: Departament de Genetica, Facultat de Biología, Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
mesh_terms: D000483:Alleles; D005776:Gaucher Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D005787:Gene Frequency; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049231:Saposins / Q000494:pharmacology; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D049231:Saposins; D051844:alpha-Synuclein; D005962:Glucosylceramidase
keywords: E326K; GBA mutations; Gaucher disease; L444P; Parkinson disease; saposin C; α-synuclein