FUS mutations in sporadic juvenile ALS: Another step toward understanding ALS pathogenesis

Neurology (Impact Factor: 8.29). 08/2010; 75(7):584-5. DOI: 10.1212/WNL.0b013e3181ed9ee4
Source: PubMed
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    ABSTRACT: The neuromuscular literature over the past 3 months has been diverse, including useful information on the epidemiology of several disorders. Our understanding of the genetics of amyotrophic lateral sclerosis continues to grow, and in the process, it makes the distinction between familial and sporadic forms of the disorder increasingly murky. Some interesting articles about peripheral neuropathy provide insight into relationships with diabetes and with Parkinson disease and summarize the state of knowledge of the increasingly complex topic of hereditary neuropathies in children. Epidemiology and electrodiagnosis of lateral femoral cutaneous neuropathy is nicely discussed in 2 articles. Several muscle diseases, including Pompe disease, sporadic inclusion body myositis, and the congenital myopathies, receive attention in articles that provide very useful information for the clinician, and there is a treatment-oriented article on dystrophinopathies, which makes for excellent reading. There are also discussions of several uncommon disorders, including a mitochondrial myopathy, periodic paralysis, and congenital myasthenic syndromes, which are helpful in providing information to clinicians who may see such disorders only infrequently.
    Preview · Article · Mar 2012 · Journal of clinical neuromuscular disease
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is incurable and characterized by progressive paralysis of the muscles of the limbs, speech and swallowing, and respiration due to the progressive degeneration of voluntary motor neurons. Clinically indistinguishable ALS can be caused by genetic mutations of Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein 43 (TDP43), or fused in sarcoma/translocated in liposarcoma (FUS/TLS), or can occur in the absence of known mutation as sporadic disease. In this study, we tested the hypothesis that FUS/TLS and TDP43 gain new pathogenic functions upon aberrant accumulation in the cytosol that directly or indirectly include misfolding of SOD1. Patient spinal cord necropsy immunohistochemistry with SOD1 misfolding-specific antibodies revealed misfolded SOD1 in perikarya and motor axons of SOD1-familial ALS (SOD1-FALS), and in motor axons of R521C-FUS FALS and sporadic ALS (SALS) with cytoplasmic TDP43 inclusions. SOD1 misfolding and oxidation was also detected using immunocytochemistry and quantitative immunoprecipitation of human neuroblastoma SH-SY5Y cells as well as cultured murine spinal neural cells transgenic for human wtSOD1, which were transiently transfected with human cytosolic mutant FUS or TDP43, or wtTDP43. We conclude that cytosolic mislocalization of FUS or TDP43 in vitro and ALS in vivo may kindle wtSOD1 misfolding in non-SOD1 FALS and SALS. The lack of immunohistochemical compartmental co-localization of misfolded SOD1 with cytosolic TDP43 or FUS suggests an indirect induction of SOD1 misfolding followed by propagation through template directed misfolding beyond its site of inception. The identification of a final common pathway in the molecular pathogenesis of ALS provides a treatment target for this devastating disease.
    Full-text · Article · Apr 2012 · PLoS ONE
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    ABSTRACT: The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease (AD) for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major diseases entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis (MND/ALS), indicating that they form a disease spectrum. In this review we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarise the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarise the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided. This article is protected by copyright. All rights reserved.
    No preview · Article · Jun 2015 · Neuropathology and Applied Neurobiology
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