Withaferin-A Treatment Alleviates TAR DNA-Binding Protein-43 Pathology and Improves Cognitive Function in a Mouse Model of FTLD.

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2020
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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. TDP-43 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-43. WFA treatment ameliorated the cognitive performance of the TDP-43 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.
Reference Key
kumar2020withaferinaneurotherapeutics Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Kumar, Sunny;Phaneuf, Daniel;Julien, Jean-Pierre;
Journal neurotherapeutics : the journal of the american society for experimental neurotherapeutics
Year 2020
DOI
10.1007/s13311-020-00952-0
URL
Keywords
autophagy nf-κb withania somnifera amyotrophic lateral sclerosis frontotemporal dementia tdp-43 withaferin-a

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