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Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis

Wright, AL, Della Gatta, PA, Le, S, Berning, BA, Mehta, P, Jacobs, KR, Gul, H, San Gil, R, Hedl, TJ, Riddell, WR, Watson, O, Keating, SS, Venturato, J, Chung, RS, Atkin, JD, Lee, A, Shi, B, Blizzard, CL ORCID: 0000-0002-9541-6943, Morsch, M and Walker, AK 2021 , 'Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis' , European Journal of Neuroscience, vol. 54, no. 6 , pp. 6237-6255 , doi:

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonlytreated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespanfor people living with ALS, and its precise mechanisms of action remainunclear. Most ALS cases are characterised by accumulation of cytoplasmicTAR DNA binding protein of 43 kDa (TDP-43), and understanding the effectsof riluzole in models that closely recapitulate TDP-43 pathology may provideinsights for development of improved therapeutics. We therefore investigatedthe effects of riluzole in female transgenic mice that inducibly express nuclearlocalisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, rNLS8, mice). Riluzole treatment from the first day ofhTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did notalter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8mice, riluzole did not ameliorate this disease-associated molecular phenotype.Likewise, riluzole did not alter the disease-associated atrophy of hindlimbmuscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late-stage disease oranimal survival. Together, we demonstrate specific glutamatergic receptoralterations and muscle fibre-type changes reminiscent of ALS in female rNLS8mice, but riluzole had no effect on these or any other disease phenotypes.Future targeting of pathways related to accumulation of TDP-43 pathologymay be needed to develop better treatments for ALS.

Item Type: Article
Authors/Creators:Wright, AL and Della Gatta, PA and Le, S and Berning, BA and Mehta, P and Jacobs, KR and Gul, H and San Gil, R and Hedl, TJ and Riddell, WR and Watson, O and Keating, SS and Venturato, J and Chung, RS and Atkin, JD and Lee, A and Shi, B and Blizzard, CL and Morsch, M and Walker, AK
Keywords: AMPA receptors, motor neuron disease, muscle atrophy, neurodegeneration, pre-clinical study
Journal or Publication Title: European Journal of Neuroscience
Publisher: Wiley-Blackwell Publishing Ltd.
ISSN: 0953-816X
DOI / ID Number:
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Copyright 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

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