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

Ian R.A. Mackenzie, Rosa Rademakers, Manuela Neumann

Research output: Contribution to journalReview articlepeer-review

551 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)995-1007
Number of pages13
JournalThe Lancet Neurology
Volume9
Issue number10
DOIs
StatePublished - Oct 1 2010

ASJC Scopus subject areas

  • Clinical Neurology

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