Author
Betsy A. Hosler
Bio: Betsy A. Hosler is an academic researcher from Harvard University. The author has contributed to research in topics: Amyotrophic lateral sclerosis & SOD1. The author has an hindex of 20, co-authored 25 publications receiving 5941 citations.
Papers
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Harvard University1, University of Massachusetts Medical School2, Massachusetts Institute of Technology3, Rhode Island Hospital4, University of Kentucky5, Tufts University6, Université de Montréal7, University of Bologna8, Children's Hospital Oakland Research Institute9, Vanderbilt University10, Northwestern University11, University of Milan12
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder Ten percent of cases are inherited; most involve unidentified genes We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders
2,387 citations
TL;DR: A 3-Mb P1-derived artificial chromosome contig spanning the MM candidate region clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb.
Abstract: Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).
835 citations
TL;DR: Two independent deletion mutations linked to ALS2 are identified in the coding exons of the new gene ALS2, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.
Abstract: Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.
608 citations
TL;DR: Information suggests it will be productive to investigate other genetic determinants in amyotrophic lateral sclerosis and to use epidemiological characteristics of the disease to help discern molecular mechanisms of motor neuron cell death.
Abstract: We registered 366 families in a study of dominantly inherited amyotrophic lateral sclerosis. Two hundred ninety families were screened for mutations in the gene encoding copper-zinc cytosolic superoxide dismutase (SOD1). Mutations were detected in 68 families. The most common SOD1 mutation is an alanine for valine substitution in codon 4 (50%). We present clinical and genetic data concerning 112 families with 395 affected individuals. The clinical characteristics of patients with familial amyotrophic lateral sclerosis arising from SOD1 mutations are similar to those lacking SOD1 defects. Mean age at onset was earlier (Wilcoxon test, p = 0.004) in the SOD1 group (46.9 years [standard deviation, 12.5] vs 50.5 years [11.5] in the non-SOD1 group). Bulbar onset was associated with a later onset age. The presence of either of two mutations, G37R and L38V, predicted an earlier age at onset. Kaplan-Meier plots demonstrated shorter survival in the SOD1 group compared with the non-SOD1 group at early survival times (Wilcoxon test, p = 0.0007). The presence of one mutation, A4V, correlated with shorter survival. G37R, G41D, and G93C mutations predicted longer survival. This information suggests it will be productive to investigate other genetic determinants in amyotrophic lateral sclerosis and to use epidemiological characteristics of the disease to help discern molecular mechanisms of motor neuron cell death.
529 citations
TL;DR: A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD in a four-generation, 50-member Scandinavian family affected with ALS and frontotemporal dementia.
Abstract: OBJECTIVE: To perform genetic linkage analysis in a family affected with ALS and frontotemporal dementia (FTD). METHODS: The authors performed a genome-wide linkage analysis of a four-generation, 5 ...
363 citations
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TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
4,153 citations
National Institutes of Health1, Cardiff University2, VU University Amsterdam3, Erasmus University Rotterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Johns Hopkins University9, Georgetown University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
3,784 citations
TL;DR: A major unifying thread of the review is a consideration of how the changes occurring during and after ischemia conspire to produce damaging levels of free radicals and peroxynitrite to activate calpain and other Ca(2+)-driven processes that are damaging, and to initiate the apoptotic process.
Abstract: This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...
2,960 citations
TL;DR: There is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators in neurodegenerative diseases.
2,838 citations
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.
2,425 citations