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


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, Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis, European Journal of Neuroscience, 54, (6) pp. 6237-6255. ISSN 0953-816X (2021) [Refereed Article]

Copyright Statement

Copyright 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd

DOI: doi:10.1111/ejn.15422


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

Item Details

Item Type:Refereed Article
Keywords:AMPA receptors, motor neuron disease, muscle atrophy, neurodegeneration, pre-clinical study
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Treatment of human diseases and conditions
UTAS Author:Blizzard, CL (Professor Leigh Blizzard)
ID Code:151832
Year Published:2021
Web of Science® Times Cited:3
Deposited By:Menzies Institute for Medical Research
Deposited On:2022-08-05
Last Modified:2022-09-08

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