Dec 07,  · A typical histological feature of inclusion body myositis (IBM) is cytoplasmic aggregation of the RNA binding protein TAR DNA-binding protein 43 (TDP-43) in the skeletal

Nov 16,  · This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration. INTRODUCTION

Feb 28,  · Patients with pathological TDP-43 showed more severe hippocampal atrophy ( Josephs et al., ) and worse performance on the Mini-Mental State Examination (MMSE), which suggested that pathological TDP-43 was highly associated with clinical signs in AD patients ( Josephs et al., ).

We discovered that TDP-43 has a functional tankyrase-binding motif; however, our data show that TDP-43 is not degraded by Tnks-1/2-dependent ubiquitination. By contrast, our results suggest that Tnks-1/2 stabilizes TDP-43 and that this may occur by inhibiting degradation of TDP-43 by the nuclear proteasome.

Past efforts to develop TDP-43-targeting therapies in ALS and FTD have been recently comprehensively reviewed [ 25, 26, 27 ]. Unfortunately, as in the broader field of neurodegenerative disease, few drugs have advanced to clinical trial, and no TDP-43-directed therapies to date have been successful in slowing or reversing the human disease.

Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%.

TDP-43 pathology-positive subjects are 10 times more likely to be cognitively impaired at death compared to TDP-43-pathology negative cases (Josephs et al., ). Nevertheless this review will focus on the loss-of-function aspect of the protein. Although how this essential RNA-binding protein contributes to the pathogenesis of ALS and FTD

TDP-43 protein is ubiquitously expressed in all cells of the body, although at differing levels and in several organs, its expression can vary substantially during development. For example, TDP-43 protein expression is significantly reduced in the brain and spinal cord during the maturation of the CNS.

Consistently, a recent review on the controversial role of TDP-43 aggregates argues that neurotoxicity may not be due merely to TDP-43 aggregation but rather to both loss and gain-of-function processes ( Hergesheimer et al., ).

Jun 26,  · In this review, we address the function of stress granules, how wild-type and mutant TDP-43 localizes to these structures, affects their formation and disassembly and the possible pathological significance of these findings. 2. Stress granule biology 2.1. Composition and assembly of stress granules

Mar 20,  · TDP-43: A Key Therapeutic Target beyond Amyotrophic Lateral Sclerosis Accumulation of TDP-43 in the cytoplasm of diseased neurons is the pathological hallmark of