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  • Oxford University Press  (3)
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  • 1
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    Conserved pharmacological rescue of hereditary spastic paraplegia-related phenotypes across model organisms (2016)
    Oxford University Press
    Details
    Publication Date: 2016-02-24
    Description: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases causing progressive gait dysfunction. Over 50 genes have now been associated with HSP. Despite the recent explosion in genetic knowledge, HSP remains without pharmacological treatment. Loss-of-function mutation of the SPAST gene, also known as SPG4, is the most common cause of HSP in patients. SPAST is conserved across animal species and regulates microtubule dynamics. Recent studies have shown that it also modulates endoplasmic reticulum (ER) stress. Here, utilizing null SPAST homologues in C. elegans , Drosophila and zebrafish, we tested FDA-approved compounds known to modulate ER stress in order to ameliorate locomotor phenotypes associated with HSP. We found that locomotor defects found in all of our spastin models could be partially rescued by phenazine, methylene blue, N -acetyl-cysteine, guanabenz and salubrinal. In addition, we show that established biomarkers of ER stress levels correlated with improved locomotor activity upon treatment across model organisms. Our results provide insights into biomarkers and novel therapeutic avenues for HSP.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Loss and gain of FUS function impair neuromuscular synaptic transmission in a genetic model of ALS (2013)
    Oxford University Press
    Details
    Publication Date: 2013-10-09
    Description: Amyotrophic lateral sclerosis (ALS) presents clinically in adulthood and is characterized by the loss of motoneurons in the spinal cord and cerebral cortex. Animal models of the disease suggest that significant neuronal abnormalities exist during preclinical stages of the disease. Mutations in the gene fused in sarcoma ( FUS ) are associated with ALS and cause impairment in motor function in animal models. However, the mechanism of neuromuscular dysfunction underlying pathophysiological deficits causing impairment in locomotor function resulting from mutant FUS expression is unknown. To characterize the cellular pathophysiological defect, we expressed the wild-type human gene (wt FUS ) or the ALS-associated mutation R521H (mut FUS ) gene in zebrafish larvae and characterized their motor (swimming) activity and function of their neuromuscular junctions (NMJs). Additionally, we tested knockdown of zebrafish fus with an antisense morpholino oligonucleotide ( fus AMO). Expression of either mut FUS or knockdown of fus resulted in impaired motor activity and reduced NMJ synaptic fidelity with reduced quantal transmission. Primary motoneurons expressing mut FUS were found to be more excitable. These impairments in neuronal function could be partially restored in fus AMO larvae also expressing wt FUS ( fus AMO+wt FUS ) but not mut FUS ( fus AMO+mut FUS ). These results show that both a loss and gain of FUS function result in defective presynaptic function at the NMJ.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis (2013)
    Oxford University Press
    Details
    Publication Date: 2013-05-21
    Description: The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C ( VAPB ) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
    Location Call Number Limitation Availability
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