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.
Highlights
TDP-43 is a DNA/RNA-binding protein localized to the nuclear compartment of the cells
The current study shows that WFA treatment reduced TDP-43 aggregates and NF-κB-dependent inflammation whereas it increased levels of LC3BIIin the brain of TDP-43G348C mice
TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, and limbic-predominant age-related TDP-43 encephalopathy (LATE) [2, 4, 10]
Summary
TDP-43 is a DNA/RNA-binding protein localized to the nuclear compartment of the cells. 50% of FTLD and 90 to 95% of ALS patients exhibit TDP-43 proteinopathy [4, 5]. Many studies have shown that boosting the clearance of TDP-43 aggregates alleviated the pathology in mice models of ALS/FTLD [8,9,10]. TDP-43 protein aggregates in the cells are targets of both autophagy and proteasome-dependent degradation [10,11,12]. A recent study has shown that TDP-43 functional loss leads to suppression of the autophagic flux [14]. Induction of autophagic markers has been shown to reduce TDP-43 pathology and to improve the cognitive function in mouse models of ALS/ FTLD [8, 9]
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