Elsevier

The Lancet Neurology

Volume 9, Issue 10, October 2010, Pages 995-1007
The Lancet Neurology

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

https://doi.org/10.1016/S1474-4422(10)70195-2Get rights and content

Summary

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.

Introduction

The presence of abnormal protein aggregates in the cytoplasm of neurons is a key characteristic of most neurodegenerative diseases. In several common disorders the disease-specific pathological protein was identified decades ago (eg, tau in neurofibrillary tangles of Alzheimer's disease and α-synuclein in Lewy bodies of Parkinson's disease), providing the logical basis for research into the underlying biological mechanisms, diagnosis, and treatment. The biochemical composition of the ubiquitinated inclusions in most cases of amyotrophic lateral sclerosis (ALS) and the most frequent pathological form of frontotemporal dementia (FTD), frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), remained unknown until the TAR DNA binding protein 43 (TDP-43)1 and the fused in sarcoma protein ([FUS] also known as translocated in liposarcoma)2, 3 were identified as disease-related proteins in these two disorders. This Review highlights the novel molecular classification of ALS and FTLD that emerged from these findings and summarises developments in the clinicopathological and genetic knowledge of disorders involving TDP-43 and FUS. Particular emphasis is placed on the molecular features and their pathomechanistic implications.

Section snippets

Novel molecular classification

ALS is the most frequent form of motor neuron disease, in which the loss of motor neurons from the brain and spinal cord leads to fatal paralysis and death, generally within 1–5 years.4 A characteristic feature of degenerating neurons is the presence of cytoplasmic inclusions positive for ubiquitin. Approximately 5% of patients with ALS have a positive family history of the disorder. The first pathological mutations identified in ALS were in SOD1,5 and account for around 20% of familial ALS

Normal function

TDP-43 is a 414 aminoacid protein encoded by TARDBP on chromosome 1p36.2, and consists of five coding and one non-coding exon (figure 2). The protein is highly conserved, widely expressed, and predominantly localised to the nucleus.22 It contains two RNA recognition motifs and a Gly-rich C-terminal region that allow it to bind single-stranded DNA, RNA, and proteins.22, 23 The exon skipping and splicing inhibitory activity requires the C-terminal region, which interacts with other members of the

Normal function

FUS is a ubiquitously expressed 526 aminoacid protein encoded by 15 exons that belongs to the FET/TET family of multifunctional DNA/RNA binding proteins (together with Ewing's sarcoma protein and the TATA-binding protein associated factor TAF15),148 and was originally discovered as a component of fusion oncogenes in human cancers.149 It contains an N-terminal Gln-Gly-Ser-Tyr-rich domain, a Gly-rich domain, an RNA recognition motif, multiple Arg-Gly-Gly repeats, a zinc finger motif,149 and a

Conclusions and future directions

The seminal discoveries of two novel key players, TDP-43 and FUS, have led to a notable shift in the understanding of pathomechanisms in ALS and FTD, and have opened new avenues for research. The structural and functional similarities of these proteins implicate alterations in processing of RNA and microRNA as key events in disease development, although the underlying functional mechanisms remain unresolved. So far, all studies except one200 have shown TDP-43 and FUS pathology to be mutually

Search strategy and selection criteria

We searched PubMed to identify full-text articles published up to June, 2010, with the terms “frontotemporal dementia”, “amyotrophic lateral sclerosis”, “TDP-43”, “TARDBP”, “FUS”, and “TLS”. Articles were also identified through searches of the authors' own article collections. Only articles published in English were reviewed.

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