Journal Article

TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia

Rademakers, Rosa, Mackenzie, Ian RA, Neumann, Manuela

2010

Overview

Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - diagnosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Animals / Dementia / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - genetics / DNA-Binding Proteins - physiology / Frontotemporal Dementia - diagnosis / Frontotemporal Dementia - genetics / Frontotemporal Dementia - metabolism / Genetic Markers - genetics / Genetic Markers - physiology / Humans / Mutation - genetics / Neurology / RNA-Binding Protein FUS - chemistry / RNA-Binding Protein FUS - genetics / RNA-Binding Protein FUS - physiology