Withaferin-A Treatment Alleviates TAR DNA-Binding Protein-43 Pathology and Improves Cognitive Function in a Mouse Model
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RESEARCH PAPER
Withaferin-A Treatment Alleviates TAR DNA-Binding Protein-43 Pathology and Improves Cognitive Function in a Mouse Model of FTLD Sunny Kumar 1 & Daniel Phaneuf 1 & Jean-Pierre Julien 1,2 Accepted: 11 October 2020 # The Author(s) 2020
Abstract Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). To date, no effective treatment is available for TDP-43 proteinopathies. Here, we tested the effects of withaferin-A (WFA), an active withanolide extracted from the medicinal herbal plant Withania somnifera, in a transgenic mouse model of FTLD expressing a genomic fragment encoding mutant TDP-43G348C. WFA treatment ameliorated the cognitive performance of the TDP-43G348C mice, and it reduced NF-κB activity and neuroinflammation in the brain. WFA alleviated TDP-43 pathology while it boosted the levels of the autophagic marker LC3BII in the brain. These data suggest that WFA and perhaps other autophagy inducers should be considered as potential therapy for neurodegenerative diseases with TDP-43 pathology. Key Words Amyotrophic lateral sclerosis . frontotemporal dementia . TDP-43 . withaferin-A . Withania somnifera . NF-κB . autophagy
Introduction TDP-43 is a DNA/RNA-binding protein localized to the nuclear compartment of the cells. TDP-43 functionally helps in the regulation of RNA transcription, splicing, and trafficking [1]. Ubiquitin-positive inclusions of TDP-43 in the cytoplasm are a hallmark of several neurodegenerative diseases including ALS, FTLD, and LATE [2, 3]. Approximately 50% of FTLD and 90 to 95% of ALS patients exhibit TDP-43 proteinopathy [4, 5]. So far, the drugs available for ALS are riluzole and edaravone [6, 7] but they extend the lifespan of patients by only a few months [6].
* Jean-Pierre Julien [email protected] 1
CERVO Brain Research Centre, Laval University, Quebec City, QC, Canada
2
Department of Psychiatry and Neuroscience, Canada Research Chair in Neurodegeneration, Université Laval, 2601, Chemin de la Canardière, Québec City, Québec G1J 2G3, Canada
Many studies have shown that boosting the clearance of TDP-43 aggregates alleviated the pathology in mice models of ALS/FTLD [8–10]. TDP-43 protein aggregates in the cells are targets of both autophagy and proteasome-dependent degradation [10–12]. Autophagy is an intracellular phenomenon, which contributes to the removal of cellular proteins and organelles by processing the formation of autophagosomes followed by lysosome-mediated degradation [13]. A recent study has shown that TDP-43 functional loss
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