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Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

ABSTRACT: Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.

SUBMITTER: Scekic-Zahirovic J

PROVIDER: S-EPMC5427169 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

Scekic-Zahirovic Jelena J Oussini Hajer El HE Mersmann Sina S Drenner Kevin K Wagner Marina M Sun Ying Y Allmeroth Kira K Dieterlé Stéphane S Sinniger Jérôme J Dirrig-Grosch Sylvie S René Frédérique F Dormann Dorothee D Haass Christian C Ludolph Albert C AC Lagier-Tourenne Clotilde C Storkebaum Erik E Dupuis Luc L

Acta neuropathologica 20170228 6

Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus ...[more]

PMID: 28243725

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Project description:BackgroundAmyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND) is a fatal disease associated with rapidly progressive disability, for which no definitive treatment as yet exists. Current treatment regimens largely focus on relieving symptoms to improve the quality of life of those affected. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND.ObjectivesTo assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no additional treatment.Search methodsOn 21 June 2016, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials' registries for ongoing or unpublished studies.Selection criteriaWe planned to include randomised controlled trials (RCTs), quasi-RCTs and cluster RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowable, provided that they were given to each group equally.Data collection and analysisWe followed standard Cochrane methodology.Main resultsNo studies were eligible for inclusion in the review. We identified four ongoing trials.Authors' conclusionsCurrently, there is a lack of high-quality evidence to guide practice on the use of cell-based therapy to treat ALS/MND.We need large, prospective RCTs to establish the efficacy of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research should be to determine the appropriate cell source, phenotype, dose, and route of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.

Project description:Amyotrophic lateral sclerosis (ALS), a common late-onset neurodegenerative disease, is associated with fronto-temporal dementia (FTD) in 3-10% of patients. A mutation in CHMP2B was recently identified in a Danish pedigree with autosomal dominant FTD. Subsequently, two unrelated patients with familial ALS, one of whom also showed features of FTD, were shown to carry missense mutations in CHMP2B. The initial aim of this study was to determine whether mutations in CHMP2B contribute more broadly to ALS pathogenesis.Sequencing of CHMP2B in 433 ALS cases from the North of England identified 4 cases carrying 3 missense mutations, including one novel mutation, p.Thr104Asn, none of which were present in 500 neurologically normal controls. Analysis of clinical and neuropathological data of these 4 cases showed a phenotype consistent with the lower motor neuron predominant (progressive muscular atrophy (PMA)) variant of ALS. Only one had a recognised family history of ALS and none had clinically apparent dementia. Microarray analysis of motor neurons from CHMP2B cases, compared to controls, showed a distinct gene expression signature with significant differential expression predicting disassembly of cell structure; increased calcium concentration in the ER lumen; decrease in the availability of ATP; down-regulation of the classical and p38 MAPK signalling pathways, reduction in autophagy initiation and a global repression of translation. Transfection of mutant CHMP2B into HEK-293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localisation demonstrated by CD63 staining and impairment of autophagy indicated by increased levels of LC3-II protein. These changes were absent in control cells transfected with wild-type CHMP2B.We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype.

Dataset Information

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

Publications

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis.

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