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

Neurotherapeutics. 2021 Jan;18(1):286-296. doi: 10.1007/s13311-020-00952-0. Epub 2020 Oct 19.

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-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.

Keywords: Amyotrophic lateral sclerosis; NF-κB; TDP-43; Withania somnifera; autophagy; frontotemporal dementia; withaferin-A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avoidance Learning / drug effects
  • Blotting, Western
  • Brain / drug effects
  • Brain / metabolism
  • Cells, Cultured
  • Cognition / drug effects*
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Female
  • Fluorescent Antibody Technique
  • Frontotemporal Lobar Degeneration / drug therapy*
  • Male
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Signal Transduction / drug effects
  • Withanolides / therapeutic use*

Substances

  • DNA-Binding Proteins
  • NF-kappa B
  • TDP-43 protein, mouse
  • Withanolides
  • withaferin A

Grant support