Abstract
BackgroundTDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile also remains unknown.MethodsBiochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used Ribotag with microarray and proteomic analysis to determine the neuronal translational profile in the mice model of ALS/FTD.ResultsHere, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induced autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function.ConclusionsOur study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.
Highlights
TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
We report for the first time that TDP-43 proteinopathy causes a translational dysregulation of selective mRNAs, including substantial repression of neurofilament mRNAs
Among the differentially regulated mRNAs, we found an upregulation of 80.23%mRNAs and a downregulation of 19.77% mRNAs in NF-L-RFP;TDP-43A315T transgenic mice when compared to NFL-rRFP mice (Fig. 7a)
Summary
TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. The impact of TDP-43 proteinopathy on neuronal translational profile in vivo remains unknown. Different studies showed that clearance of excess cytoplasmic TDP-43 ameliorated the disease pathology in such mouse models of ALS [3, 14, 15]. We reported that AAVmediated delivery of a single-chain antibody capable to block TDP-43 interaction with p65 NF-ĸB led to reduction of NF-ĸB activity and of TDP-43 aggregates in mouse models of ALS/FTD [3]. Withaferin-A was found to disrupt the NF-κB essential modulator (NEMO) reorganization into ubiquitin-based signaling structures by covalently modifying Cysteine-397, producing a lack of IKKβ activation [19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
