FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons.

FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons. Brain Res. 2018 Apr 03;: Authors: Machamer JB, Woolums BM, Fuller G, Lloyd TE Abstract Mutations in the nuclear localization signal of the RNA binding protein FUS cause both Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). These mutations result in a loss of FUS from the nucleus and the formation of FUS-containing cytoplasmic aggregates in patients. To better understand the role of cytoplasmic FUS mislocalization in the pathogenesis of ALS, we identified a population of cholinergic neurons in Drosophila that recapitulate these pathologic hallmarks. Expression of mutant FUS or the Drosophila homolog, Cabeza (Caz), in class IV dendritic arborization neurons results in cytoplasmic mislocalization and axonal transport to presynaptic terminals. Interestingly, overexpression of FUS or Caz causes the progressive loss of neuronal projections, reduction of synaptic mitochondria, and the appearance of large calcium transients within the synapse. Additionally, we find that overexpression of mutant but not wild type FUS results in a reduction in presynaptic Synaptotagmin, an integral component of the neurotransmitter release machinery, and mutant Caz specifically disrupts axonal transport and induces hyperexcitability. These results suggest that FUS/Caz overexpression disrupts neuronal function through multiple mechanisms, and that ALS-causing mutations impair t...
Source: Brain Research - Category: Neurology Authors: Tags: Brain Res Source Type: research

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C9orf72-mediated ALS and FTD: multiple pathways to disease, Published online: 17 August 2018; doi:10.1038/s41582-018-0047-2Repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Balendra and Isaacs review the pathological and mechanistic features of C9orf72-associated ALS and FTD, highlighting loss-of-function, gain-of-function and downstream mechanisms.
Source: Nature Reviews Neurology - Category: Neurology Authors: Source Type: research
The analysis of underivatized β-Methylamino-L-alanine (BMAA), BAMA, AEG &2,4-DAB in Pteropus mariannus mariannus specimens using HILIC-LC-MS/MS. Toxicon. 2018 Aug 10;: Authors: Foss AJ, Chernoff N, Aubel MT Abstract β-Methylamino-L-alanine (BMAA) has been identified as the potential cause of the amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) observed in the Chamorro people of Guam. The principal hypothesis for BMAA exposure and intoxication relies on the biomagnification of BMAA in flying fox specimens ingested by the Chamorro people. Although high levels of BMAA w...
Source: Toxicon - Category: Toxicology Authors: Tags: Toxicon Source Type: research
s MH, Vorgerd M, Eichinger L, Schröder R Abstract Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VC...
Source: Biochemical and Biophysical Research communications - Category: Biochemistry Authors: Tags: Biochem Biophys Res Commun Source Type: research
ger V Abstract Following the involvement of CHCHD10 in FrontoTemporal-Dementia-Amyotrophic Lateral Sclerosis (FTD-ALS) clinical spectrum, a founder mutation (p.Gly66Val) in the same gene was identified in Finnish families with late-onset spinal motor neuronopathy (SMAJ). SMAJ is a slowly progressive form of spinal muscular atrophy with a life expectancy within normal range. In order to understand why the p.Ser59Leu mutation, responsible for severe FTD-ALS, and the p.Gly66Val mutation could lead to different levels of severity, we compared their effects in patient cells. Unlike affected individuals bearing the p.Se...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
In this study, we screened C9orf72 in 189 Italian patients with primary progressive MS (PPMS), a rare clinical form characterized by less inflammation over neurodegenerative features. We failed to detect C9orf72 RE, but a significant representation of intermediate alleles (≥20 units) was observed in our PPMS cohort (2.1%) compared to healthy controls (0%, p
Source: Multiple Sclerosis and Related Disorders - Category: Neurology Source Type: research
Publication date: 24 July 2018Source: Cell Reports, Volume 24, Issue 4Author(s): Eva-Maria Hock, Zuzanna Maniecka, Marian Hruska-Plochan, Stefan Reber, Florent Laferrière, Sonu Sahadevan M.K., Helena Ederle, Lauren Gittings, Lucas Pelkmans, Luc Dupuis, Tammaryn Lashley, Marc-David Ruepp, Dorothee Dormann, Magdalini PolymenidouSummaryThe primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress gra...
Source: Cell Reports - Category: Cytology Source Type: research
Contributors : E M Tank ; C Figueroa-Romero ; L M Hinder ; K Bedi ; H C Archbold ; X Li ; K Weskamp ; N Safren ; X Paez-Colasante ; C Pacut ; S Thumma ; M T Paulsen ; K Guo ; J Hur ; M Ljungman ; E L Feldman ; S J BarmadaSeries Type : OtherOrganism : Homo sapiensAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA binding protein TDP-43. TDP-43 regulatesRNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We used Bru-seq and BruChase-seq to assessgenome-wide RNA stabilityinALS patient-derived cells,demonstratingp...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens Source Type: research
Abnormalities in nucleic acid processing are associated with the development of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations inMatrin 3 (MATR3), a poorly understood DNA- and RNA-binding protein, cause familial ALS/FTD, and MATR3 pathology is a feature of sporadic disease, suggesting that MATR3 dysfunction is integrally linked to ALS pathogenesis. Using a rat primary neuron model to assess MATR3-mediated toxicity, we noted that neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity. MATR3 ’s zinc finger domains partially m...
Source: eLife - Category: Biomedical Science Tags: Cell Biology Neuroscience Source Type: research
Abstract Over the past 20 years, the concept of mammalian autophagy as a nonselective degradation system has been repudiated, due in part to important discoveries in neurodegenerative diseases, which opened the field of selective autophagy. Protein aggregates and damaged mitochondria represent key pathological hallmarks shared by most neurodegenerative diseases. The landmark discovery in 2007 of p62/SQSTM1 as the first mammalian selective autophagy receptor defined a new family of autophagy-related proteins that serve to target protein aggregates, mitochondria, intracellular pathogens and other cargoes to the co...
Source: Neurobiology of Disease - Category: Neurology Authors: Tags: Neurobiol Dis Source Type: research
t S Abstract VCP/p97 (valosin containing protein) is a key regulator of cellular proteostasis. It orchestrates protein turnover and quality control in vivo, processes fundamental for proper cell function. In humans, mutations in VCP lead to severe myo- and neuro-degenerative disorders such as inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS) or and hereditary spastic paraplegia (HSP). We analyzed here the in vivo role of Vcp and its novel interactor Washc4/Swip (WASH complex subunit 4) in the vertebrate model zebrafish (Danio rerio). We...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
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