TY - JOUR
T1 - TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
AU - Mackenzie, Ian R.A.
AU - Rademakers, Rosa
AU - Neumann, Manuela
PY - 2010/10
Y1 - 2010/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77956850818&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956850818&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(10)70195-2
DO - 10.1016/S1474-4422(10)70195-2
M3 - Review article
C2 - 20864052
AN - SCOPUS:77956850818
SN - 1474-4422
VL - 9
SP - 995
EP - 1007
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 10
ER -