TY - JOUR
T1 - A new subtype of frontotemporal lobar degeneration with FUS pathology
AU - Neumann, Manuela
AU - Rademakers, Rosa
AU - Roeber, Sigrun
AU - Baker, Matt
AU - Kretzschmar, Hans A.
AU - MacKenzie, Ian R.A.
N1 - Funding Information:
Canadian Institutes of Health Research (grant number 74580 to I.M.); the Pacific Alzheimer Research Foundation (to I.M. and R.R.); National Institute of Health (grant number P50 AG16574 to R.R.); the Deutsche Forschungsgemeinschaft (SFB 596 to M.N.); the Stavros-Niarchos Foundation (to M.N.); the Synapsis Foundation (to M.N.); and the German Brain Bank ‘BrainNet’ (to H.K.).
PY - 2009/11
Y1 - 2009/11
N2 - Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related conditions.
AB - Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The neuropathology associated with most FTD is characterized by abnormal cellular aggregates of either transactive response DNA-binding protein with Mr 43 kDa (TDP-43) or tau protein. However, we recently described a subgroup of FTD patients, representing around 10, with an unusual clinical phenotype and pathology characterized by frontotemporal lobar degeneration with neuronal inclusions composed of an unidentified ubiquitinated protein (atypical FTLD-U; aFTLD-U). All cases were sporadic and had early-onset FTD with severe progressive behavioural and personality changes in the absence of aphasia or significant motor features. Mutations in the fused in sarcoma (FUS) gene have recently been identified as a cause of familial amyotrophic lateral sclerosis, with these cases reported to have abnormal cellular accumulations of FUS protein. Because of the recognized clinical, genetic and pathological overlap between FTD and amyotrophic lateral sclerosis, we investigated whether FUS might also be the pathological protein in aFTLD-U. In all our aFTLD-U cases (n = 15), FUS immunohistochemistry labelled all the neuronal inclusions and also demonstrated previously unrecognized glial pathology. Immunoblot analysis of protein extracted from post-mortem aFTLD-U brain tissue demonstrated increased levels of insoluble FUS. No mutations in the FUS gene were identified in any of our patients. These findings suggest that FUS is the pathological protein in a significant subgroup of sporadic FTD and reinforce the concept that FTD and amyotrophic lateral sclerosis are closely related conditions.
KW - FUS
KW - Frontotemporal dementia
KW - Frontotemporal lobar degeneration
KW - Fused in sarcoma
KW - TLS
KW - Translocated in liposarcoma
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U2 - 10.1093/brain/awp214
DO - 10.1093/brain/awp214
M3 - Article
C2 - 19674978
AN - SCOPUS:70350673956
SN - 0006-8950
VL - 132
SP - 2922
EP - 2931
JO - Brain
JF - Brain
IS - 11
ER -