ORCID Profile
0000-0002-5062-3156
Current Organisations
Université François-Rabelais
,
Centre Hospitalier Régional Universitaire de Tours
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Publisher: Informa UK Limited
Date: 13-07-2017
DOI: 10.1080/21678421.2017.1349152
Abstract: Mutations in the TAR-DNA Binding Protein-43 (TDP-43) encoding the TARDBP gene are present in amyotrophic lateral sclerosis (ALS). TDP-43 is the major component of ubiquitin-positive inclusions in motor neurons in ALS patients. We report here a novel heterozygous missense mutation in TARDBP in an ALS patient presenting a rapid form of ALS. This mutation p.N259S is located within the RNA recognition motif 2 (RRM2) in very close proximity with nucleotides in RNA. It is the first time a mutation was reported in this RRM2 domain of TDP-43. Expression of TDP-43
Publisher: Wiley
Date: 30-08-2017
DOI: 10.1002/GLIA.23212
Publisher: Oxford University Press (OUP)
Date: 04-2019
DOI: 10.1093/BRAIN/AWZ078
Publisher: Springer Science and Business Media LLC
Date: 21-03-2017
DOI: 10.1038/NCOMMS14774
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique in iduals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6 P =1 × 10 −4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS ( P =8.4 × 10 −7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
Publisher: Springer Science and Business Media LLC
Date: 15-11-2019
DOI: 10.1007/S12035-019-01810-7
Abstract: In amyotrophic lateral sclerosis, motor neurons undergoing degeneration are characterized by the presence of cytoplasmic aggregates containing TDP-43 protein. SUMOylation, a posttranslational modification of proteins, has been previously implicated in the formation of aggregates positives for SOD1, another protein enriched in a subset of ALS patients. We show in this study that TDP-43 is also a target of SUMOylation. The inhibition of the first step of the SUMOylation process by anacardic acid significantly reduces the presence of TDP-43 aggregates and improves neuritogenesis and cell viability in vitro. Interestingly, the mutation of the unique SUMOylation site on TDP-43, using site-directed mutagenesis, modifies the intracellular localization of TDP-43 aggregates. Instead of being cytoplasmic where they are associated with toxic effects, they are located inside the nucleus. This change of localization results in improvement in cell viability and in global cellular functions. Our results implicate the SUMOylation site of TDP-43 in the formation of cytoplasmic TDP-43 aggregates, a hallmark of ALS, and thus identifies this region as a new target for novel therapeutic strategies.
Publisher: Springer Science and Business Media LLC
Date: 25-07-2016
DOI: 10.1038/NG.3622
Publisher: Springer Science and Business Media LLC
Date: 10-01-2018
DOI: 10.1007/S12035-017-0856-0
Abstract: Amyotrophic lateral sclerosis (ALS) is a disease caused by the degeneration of motor neurons (MNs) leading to progressive muscle weakness and atrophy. Several molecular pathways have been implicated, such as glutamate-mediated excitotoxicity, defects in cytoskeletal dynamics and axonal transport, disruption of RNA metabolism, and impairments in proteostasis. ALS is associated with protein accumulation in the cytoplasm of cells undergoing neurodegeneration, which is a hallmark of the disease. In this review, we focus on mechanisms of proteostasis, particularly protein degradation, and discuss how they are related to the genetics of ALS. Indeed, the genetic bases of the disease with the implication of more than 30 genes associated with familial ALS to date, together with the important increase in understanding of endoplasmic reticulum (ER) stress, proteasomal degradation, and autophagy, allow researchers to better understand the mechanisms underlying the selective death of motor neurons in ALS. It is clear that defects in proteostasis are involved in this type of cellular degeneration, but whether or not these mechanisms are primary causes or merely consequential remains to be clearly demonstrated. Novel cellular and animal models allowing chronic expression of mutant proteins, for ex le, are required. Further studies linking genetic discoveries in ALS to mechanisms of protein clearance will certainly be crucial in order to accelerate translational and clinical research towards new therapeutic targets and strategies.
Location: Israel
No related grants have been discovered for Christian Andres.