7 research outputs found
Study of pathway of SUMOylation in Amyotrophic Lateral Sclerosis associated with SOD1 gene mutation
La sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative des motoneurones impliquant des facteurs environnementaux et génétiques. Notre étude porte sur l’étude des relations entre la voie de la SUMOylation post-Traductionnelle des protéines et les effets du stress oxydant et de mutants SOD1. Nous montrons tout d’abord que 2 nouveaux mutants, SOD1V31A et SOD1E121G identifiés chez des patients SLA à évolution lente, entraîne la formation d’agrégats cellulaires Ub/SUMO dans la formation des agrégats était suggérée. Nous montrons 1) que les NSC-34 exposées à un stress oxydant et exprimant SOD1 mutée présentent une modification d’expression de plusieurs gènes des voies de l’Ub/SUMO ; 2) que l’expression de SOD1 mutée réduit le pool de protéine SUMO-1 libre dans les cellules motoneuronales, possible conséquence d’une séquestration dans les agrégats ; 3) qu’inhiber la SUMOylation de SOD1 mutée réduit la quantité de cellules avec agrégats. Nos résultats indiquent qu’une meilleure connaissance de la voie de SUMO pourrait conduire à de nouvelles cibles thérapeutiques intéressantes dans la SLA.Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of motor neurones involving a combination of environmental and genetics factors. Ours work focuses on the relathionship between the SUMOylation pathway and the effects of oxidative stress and SOD1 mutants. We first show that 2 new mutants, SOD1V31A and SOD1E121G identified in ALS patients with a slowly progressive disease, induce the formation of Ub/SUMO positive aggregates in motor neuronal cells NSC-34. The implication of the Ub/SUMO pathways has been proposed in the formation of aggregates in ALS. We show 1) modification of expression of several genes of the Ub/SUMO pathways in NSC-34 exposed to oxidative stress and expressing various mutated SOD1 proteins; 2) that the expression of mutants SOD1 reduces free-SUMO1 concentration in motor neuronal cell, perhaps by a sequestration in aggregates; 3) that the inhibition of SUMIylation of various mutants SOD1 reduces the amount of cells with aggregates. Our results support further studies on the SUMO pathway that may lead to new therapeutics targets in ALS
Dysregulations of Expression of Genes of the Ubiquitin/SUMO Pathways in an In Vitro Model of Amyotrophic Lateral Sclerosis Combining Oxidative Stress and SOD1 Gene Mutation
Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations
Study of Ubiquitin Pathway Genes in a French Population with Amyotrophic Lateral Sclerosis: Focus on <i>HECW1</i> Encoding the E3 Ligase NEDL1
The ubiquitin pathway, one of the main actors regulating cell signaling processes and cellular protein homeostasis, is directly involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). We first analyzed, by a next-generation sequencing (NGS) strategy, a series of genes of the ubiquitin pathway in two cohorts of familial and sporadic ALS patients comprising 176 ALS patients. We identified several pathogenic variants in different genes of this ubiquitin pathway already described in ALS, such as FUS, CCNF and UBQLN2. Other variants of interest were discovered in new genes studied in this disease, in particular in the HECW1 gene. We have shown that the HECT E3 ligase called NEDL1, encoded by the HECW1 gene, is expressed in neurons, mainly in their somas. Its overexpression is associated with increased cell death in vitro and, very interestingly, with the cytoplasmic mislocalization of TDP-43, a major protein involved in ALS. These results give new support for the role of the ubiquitin pathway in ALS, and suggest further studies of the HECW1 gene and its protein NEDL1 in the pathophysiology of ALS
Phenotypic and genotypic studies of ALS cases in ALS-SMA families
International audienceBACKGROUND:Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most frequent motor neuron disorders in adulthood and infancy, respectively. There is a growing literature supporting common pathophysiological patterns between those disorders. One important clinical issue for that is the co-occurrence of both diseases within a family.OBJECTIVES:To collect families in which ALS and SMA patients co-exist and describe the phenotype and the genotype of ALS patients.PATIENTS AND METHODS:Nine families with co-occurrence of SMA and ALS have been gathered over the last 15 years. Epidemiological, phenotype and genetic status were collected.RESULTS:Out of the nine families, six corresponded to the criteria of familial ALS (FALS). Clinical data were available for 11 patients out of the 15 ALS cases. Mean age of onset was 58.5 years, site of onset was lower limbs in nine cases (81.8%), median duration was 22 months. Four ALS patients carried a mutation: three mutations in SOD1 gene (G147N in two cases and one with E121G) and one repeat expansion in the C9ORF72 gene. Three patients had abnormal SMN1 copy numbers.CONCLUSIONS:While the high proportion of familial history of ALS cases in these ALS-SMA pedigrees could have suggested that these familial clusters of the two most frequent MND rely on a genetic background, we failed to exclude that this occurred by chance