title: Withania somnifera Reverses Transactive Response DNA Binding Protein 43 Proteinopathy in a Mouse Model of Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration.
abstract: Abnormal cytoplasmic mislocalization of transactive response DNA binding protein 43 (TARDBP or TDP-43) in degenerating neurons is a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Our previous work suggested that nuclear factor kappa B (NF-κB) may constitute a therapeutic target for TDP-43-mediated disease. Here, we investigated the effects of root extract of Withania somnifera (Ashwagandha), an herbal medicine with anti-inflammatory properties, in transgenic mice expressing a genomic fragment encoding human TDP-43A315Tmutant. Ashwagandha extract was administered orally to hTDP-43A315Tmice for a period of 8 weeks starting at 64 and 48 weeks of age for males and females, respectively. The treatment of hTDP-43A315Tmice ameliorated their motor performance on rotarod test and cognitive function assessed by the passive avoidance test. Microscopy examination of tissue samples revealed that Ashwagandha treatment of hTDP-43A315Tmice improved innervation at neuromuscular junctions, attenuated neuroinflammation, and reduced NF-κB activation. Remarkably, Ashwagandha treatment reversed the cytoplasmic mislocalization of hTDP-43 in spinal motor neurons and in brain cortical neurons of hTDP-43A315Tmice and it reduced hTDP-43 aggregation. In vitro evidence is presented that the neuronal rescue of TDP-43 mislocalization may be due to the indirect effect of factors released from microglial cells exposed to Ashwagandha. These results suggest that Ashwagandha and its constituents might represent promising therapeutics for TDP-43 proteinopathies.
authors.affiliation: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Québec City, G1J 2G3, Canada.
authors.forename: Kallol
authors.initials: K
authors.lastname: Dutta
authors.affiliation: Department of Biological Sciences, University of South Carolina, Columbia, SC, 29208, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Patel
authors.affiliation: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Québec City, G1J 2G3, Canada.
authors.forename: Reza
authors.initials: R
authors.lastname: Rahimian
authors.affiliation: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Québec City, G1J 2G3, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Phaneuf
authors.affiliation: Centre de Recherche de l'Institut Universitaire en Santé Mentale de Québec, Québec City, G1J 2G3, Canada. jean-pierre.julien@fmed.ulaval.ca.|Department of Psychiatry and Neuroscience, Université Laval, Québec City, G1V 0A6, Canada. jean-pierre.julien@fmed.ulaval.ca.
authors.forename: Jean-Pierre
authors.identifier: http://orcid.org/0000-0002-9072-5667
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000517:prevention & control; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010936:Plant Extracts / Q000008:administration & dosage* / Q000302:isolation & purification / Q000627:therapeutic use; D045442:Rotarod Performance Test; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D032341:Withania
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D010936:Plant Extracts; C578077:Tardbp protein, mouse; C030693:Ashwagandha
keywords: Amyotrophic lateral sclerosis; NF-κB.; TDP-43; Withania somnifera