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]
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.
AMPA receptors, motor neuron disease, muscle atrophy, neurodegeneration, pre-clinical study