Elisabeth Leroy

The ubiquitin pathway in Parkinson's disease

Mutations of the α-synuclein gene, have been identified in some familial forms of Parkinsons disease, and α-synuclein protein has been shown to accumulate in the brains of patients with the disease. These findings suggest that Parkinsons disease may be caused by the abnormal aggregation of α-synuclein protein. Here we have identified in a German family with Parkinsons disease a missense mutation in the ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene. We show that this mutation, Ile93Met, causes a partial loss of the catalytic activity of this thiol protease, which could lead to aberrations in the proteolytic pathway and aggregation of proteins.

Identification, localization and characterization of the human γ-synuclein gene

We have identified and characterized a new member of the human synuclein gene family, γ-synuclein (SNCG). This gene is composed of five exons, which encode a 127 amino acid protein that is highly homologous to α-synuclein, which is mutated in some Parkinson’s disease families, and to β-synuclein. The γ-synuclein gene is localized to chromosome 10q23 and is principally expressed in the brain, particularly in the substantia nigra. We have determined its genomic sequence, and established conditions for sequence analysis of each of the exons. The γ-synuclein gene, also known as BCSG1, was recently found to be overexpressed in advanced infiltrating carcinoma of the breast. Our survey of the EST database indicated that it might also be overexpressed in an ovarian tumor.

Mutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients.

Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether mutations in the UCHL1 gene are causative for Parkinsons disease (PD) a detailed mutation analysis was performed in a large sample of German sporadic and familial PD patients. We found no disease-causing mutation in the coding region of the UCHL1 gene. Direct sequencing revealed six intronic polymorphisms in the UCHL1 gene. Analysis of an S18Y polymorphism in exon 3 of the UCHL1 gene in sporadic PD patients and controls showed carriers of allele 2 (tyrosine) significantly less frequent in patients with a reduced risk of 0.57 (CI = 0.36–0.88; p = 0.012, pc = 0.047, χ2 = 6.31). Our study shows that sequence variations in the coding region of UCHL1 are a rare event. A protective effect of a certain UCHL1 variant in the pathogenesis of sporadic PD is suggested, underlining the relevance of UCHL1 in neurodegeneration.

Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson’s disease

Abstract Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson’s disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson’s disease.

Genetic Analysis of Families with Parkinson Disease that Carry the Ala53Thr Mutation in the Gene Encoding α-Synuclein

We wish to thank Drs. C. Bissas, N. Georgopoulos, P. Ghikas, C. Kremmydas, P. Leonardos, S. Papapetropoulos, and, last but not least, A. Protonotariou, for their great help in sample collection. This work was supported by European Framework Program EPET II grant 236/234/603 to G.M.M.

The G209A mutation in the alpha-synuclein gene in Brazilian families with Parkinson's disease

Recentemente foi detectada mutacao missense G209A no gene da alfa-sinucleina em uma grande familia com doenca de Parkinson (DP) de Contursi, Italia. Este estudo tem o objetivo de determinar se a mutacao G209A esta presente em 10 familias brasileiras com DP. Pacientes com DP foram recrutados em clinicas de disturbio do movimento no Brasil. O criterio de inclusao no estudo foi a presenca de dois ou mais familiares acometidos pela DP. A mutacao G209A do gene da alfa-sinucleina foi pesquisada usando a tecnica de reacao em cadeia de polimerase e a enzima de restricao Tsp45I. Foram estudados 10 pacientes de familias nao-relacionadas. A idade media do inicio dos sintomas da DP foi 42,7 anos. Nao encontramos a mutacao estudada neste grupo de pacientes. Nossos resultados sugerem que a mutacao G209A e incomum em familias brasileiras com DP.A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinsons disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.

Mutação G209A no gene da alfa-sinucleína em famílias brasileiras com doença de Parkinson

Recentemente foi detectada mutacao missense G209A no gene da alfa-sinucleina em uma grande familia com doenca de Parkinson (DP) de Contursi, Italia. Este estudo tem o objetivo de determinar se a mutacao G209A esta presente em 10 familias brasileiras com DP. Pacientes com DP foram recrutados em clinicas de disturbio do movimento no Brasil. O criterio de inclusao no estudo foi a presenca de dois ou mais familiares acometidos pela DP. A mutacao G209A do gene da alfa-sinucleina foi pesquisada usando a tecnica de reacao em cadeia de polimerase e a enzima de restricao Tsp45I. Foram estudados 10 pacientes de familias nao-relacionadas. A idade media do inicio dos sintomas da DP foi 42,7 anos. Nao encontramos a mutacao estudada neste grupo de pacientes. Nossos resultados sugerem que a mutacao G209A e incomum em familias brasileiras com DP.A missense G209A mutation of the alpha-synuclein gene was recently described in a large Contursi kindred with Parkinsons disease (PD). The objective of this study is to determine if the mutation G209A of the alpha-synuclein gene was present in 10 Brazilian families with PD. PD patients were recruited from movement disorders clinics of Brazil. A family history with two or more affected in relatives was the inclusion criterion for this study. The alpha-synuclein G209A mutation assay was made using polymerase chain reaction and the restriction enzyme Tsp45I. Ten patients from 10 unrelated families were studied. The mean age of PD onset was 42.7 years old. We did not find the G209A mutation in our 10 families with PD. Our results suggest that alpha-synuclein mutation G209A is uncommon in Brazilian PD families.