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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ron;imić G Abstract Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2-10 hexanucleoti...
Source: Behavioural Neurology - Category: Neurology Authors: Tags: Behav Neurol Source Type: research
CONCLUSIONS: Ultrasound-guided botulinum toxin injections into the parotid and submandibular glands seem to be a safe and effective therapy for the treatment of drooling. Further long-term prospective studies with varying doses are warranted. PMID: 30772963 [PubMed - in process]
Source: The Israel Medical Association Journal - Category: General Medicine Tags: Isr Med Assoc J Source Type: research
Abstract Cellular adaption to nutrient stress is exquisitely regulated, and its dysregulation could underlie human diseases including neurodegeneration. C9orf72 is linked to the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as rare cases of other neurological disorders. Recent studies have implicated C9orf72 functions in the autophagy-lysosome pathway, but the exact roles of C9orf72 remain unclear. We found that C9orf72 is required for the lysosomal targeting and degradation of CARM1, which is an important epigenetic regulator of macroautophagy/autophagy and lip...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
A G4C2 hexanucleotide repeat expansion in the noncoding region of C9orf72 is the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Putative disease mechanisms underlyin...
Source: Molecular Neurodegeneration - Category: Neurology Authors: Tags: Research article Source Type: research
How hexanucleotide GGGGCC (G4C2) repeat expansions in C9orf72 cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is not understood. We developed a mouse model engineered to express poly(PR), a proline-arginine (PR) dipeptide repeat protein synthesized from expanded G4C2 repeats. The expression of green fluorescent protein–conjugated (PR)50 (a 50-repeat PR protein) throughout the mouse brain yielded progressive brain atrophy, neuron loss, loss of poly(PR)-positive cells, and gliosis, culminating in motor and memory impairments. We found that poly(PR) bound DNA, localized to heterochromatin, an...
Source: ScienceNOW - Category: Science Authors: Tags: Medicine, Diseases, Online Only r-articles Source Type: news
Publication date: Available online 11 February 2019Source: Journal of Molecular BiologyAuthor(s): Henriette Haukedal, Kristine FreudeAbstractAmyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD) are neurodegenerative disorders with clear similarities regarding their clinical, genetic and pathological features. Both are progressive, lethal disorders, with no current curative treatment available. Several genes correlated with ALS and FTD are implicated in the same molecular pathways. Strikingly, many of these genes are not exclusively expressed in neurons, but also in glial cells, suggesting a multicellular p...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research
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Source: International Journal of Neuroscience - Category: Neuroscience Authors: Source Type: research
AbstractWith continuing cooperation from 18 domestic and international brain banks over the last 36  years, we have analyzed the aluminum content of the temporal lobe neocortex of 511 high-quality human female brain samples from 16 diverse neurological and neurodegenerative disorders, including 2 groups of age-matched controls. Temporal lobes (Brodmann areas A20–A22) were selected for analysis because of their availability and their central role in massive information-processing operations including efferent-signal integration, cognition, and memory formation. We used the analytical technique of (i) Zeeman-type ...
Source: Molecular Neurobiology - Category: Neurology Source Type: research
In this study, we show that calorie restriction is protective against age-related increases in senescence and microglia activation and pro-inflammatory cytokine expression in an animal model of aging. Further, these protective effects mitigated age-related decline in neuroblast and neuronal production, and enhanced olfactory memory performance, a behavioral index of neurogenesis in the SVZ. Our results support the concept that calorie restriction might be an effective anti-aging intervention in the context of healthy brain aging. Greater Modest Activity in Late Life Correlates with Lower Incidence of Dementia ...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Abstract Mutations in C9orf72 leading to hexanucleotide expansions are the most common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A phenotype resembling ALS and FTD is seen in transgenic mice overexpressing the hexanucleotide expansions, but is absent in C9orf72-deficient mice. Thus, the exact function of C9orf72 in neurons and how loss of C9orf72 may contribute to neuronal dysfunction remains to be clearly defined. Here, we showed that primary hippocampal neurons cultured from c9orf72 knockout mice have reduced dendritic arborization and spine density. Quantitative p...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
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