Improving Motor Function in Amyotrophic Lateral Sclerosis: The impact of Triumeq on a TDP-43 mouse model

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by the accumulation of TAR DNA Binding Protein (43kDa; TDP-43) within the cytoplasm of neurons. Endogenous retroviruses (ERVs) have been implicated in ALS pathology and the application of antiretroviral therapy, specifically Triumeq, has been proposed for treatment of ALS. However, evidence to support the actions of Triumeq in ALS is lacking. Methods This study utilised the doxycycline (Dox)-suppressible rNLS8 TDP-43 expression mouse model to investigate the effects of Triumeq on ALS disease pathology and progression. In this model, TDP-43 accumulation in the cytoplasm was induced after removal of Dox. Disease progression was assessed through measures of body weight, neurological score, motor function and inflammatory marker expression. Results Triumeq treatment significantly improved motor function early on in the disease course but did not impact other disease progression markers or disease endpoint. In this TDP-43 ALS mouse model, there was a positive association of TDP-43 mRNA levels with transcription factor ATF4, and inflammatory markers CXCL10 and IRF-1, and Triumeq treatment negated this association. Conclusions Triumeq treatment transiently improved motor function and influenced TDP-43 associated inflammatory gene expression in an ALS mouse model. These findings support the potential use of Triumeq in treating TDP-43-associated ALS and supports further investigation to better understand if the beneficial actions of Triumeq are via impact on ERVs or indirectly through disruption of TDP-43-driven inflammation in ALS.