TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia.
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.
Mackenzie
Ian Ra
IR
Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
Rademakers
Rosa
R
Neumann
Manuela
M
D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D057180:Frontotemporal Dementia / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D005819:Genetic Markers / Q000235:genetics / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D004268:DNA-Binding Proteins; D005819:Genetic Markers; D034702:RNA-Binding Protein FUS