Induction of autophagy mitigates TDP-43 pathology in mouse models of ALS/FTD

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It has been suggested that autophagy insuficiency occurring during aging may contribute to increase of misfolded proteins. TDP-43 aggregates in motor neurons are found in the majority of ALS patients and in other neurodegenerative diseases. TDP-43 protein is involved in the regulation of RNA processing and splicing as well as in chromatin condensation.

In this article Sunny Kumar in Jean-Pierre Julien's lab in Laval's university, studied the translational profiles of neurons in one-year old transgenic mice expressing hTDP-43 A315T mutant, a model of ALS/FTD.

Dr. Jean-Pierre Julien’s is also ImStar Chief Scientific Officer research.

Measuring RNA from a defined subset of cells derived from a complex tissue is a challenge. The RiboTag method allows for immunoprecipitation of ribosome-associated RNA from specific cells within complex tissues .

Neurofilaments are major cytoskeletal components in neurons. Neurofilament disorganization can contribute to neuronal dysfunction and death. Transgenic mouse studies have highlighted the importance of Neurofilament protein stoichiometry for correct assembly and transport. Previous reports showed that TDP-43 can bind and stabilize Neurofilament mRNAs.

Kumar and al report the therapeutic effects of a novel withaferin-A analog, called IMS-088, in transgenic mice expressing hTDP-43 mutants Withaferin-A, a compound extracted from the medicinal plant Withania somnifera has emerged with a therapeutic potential as inhibitor of NF-κB signalling pathway and as inducer of autophagy. Withaferin-A treatment conferred protection in two mouse models of ALS. Withanolides are a group of at least 300 naturally occurring steroids . They occur as secondary metabolites primarily in genera of the Nightshade family. It remains unknown to what end withanolides are produced; they may act as a deterrent for feeding insect larvae and other herbivores.

Despite beneficial properties of withaferin-A, this compound can induce cell death at high dose or prolonged treatment. Addition of methoxy group to withaferin A significantly reduced toxic properties.

The IMS-088 compound obtained from IMSTAR therapeutics is basically the 4-O- methyl withaferin-A which is better tolerated at high doses than withaferin-A in mice. A pharmacokinetic study with 14 C-labeled-IMS-088 revealed that this novel analog penetrates the blood brain barrier after oral intake

The present study shows that oral administration of IMS-088 for 8 weeks in transgenic mouse models with TDP-43 proteinopathy led to reduction of cytoplasmic TDP-43 aggregates in the brain and spinal cord The IMS-088 treatment increased the levels of Beclin-1 and LC3BII which are autophagic markers Of particular interest was the finding that IMS-088 rescued the translational repression of Neurofilament proteins in the brain of the mice expressing mutant hTDP-43 Treatment of mice expressing mutant hTDP-43 with IMS-088, an inhibitor of NF-κB activity, led to reduction of microgliosis and astrogliosis. NF-κB is a transcription factor playing a key role in inflammatory responses including genes encoding cytokines and chemokines. Microglia-specific inhibition of NF-κB pathway has also shown to attenuate neuroinflammation and extended survival by several weeks in the SOD1 G93A mice. From these results, the scientists conclude that clearance of cytoplasmic TDP-43 by IMS-088 in the mouse models is likely the result of a boost of autophagic activity


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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