Abstract
Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. Until recently, the underlying cause was known in only a minority of cases that were associated with abnormalities of the tau protein or gene. In 2006, however, mutations in the progranulin gene were discovered as another important cause of familial FTD. That same year, TAR DNA-binding protein 43 (TDP-43) was identified as the pathological protein in the most common subtypes of FTD and amyotrophic lateral sclerosis (ALS). Since then, substantial efforts have been made to understand the functions and regulation of progranulin and TDP-43, as well as their roles in neurodegeneration. More recently, other DNA/RNA binding proteins (FET family proteins) have been identified as the pathological proteins in most of the remaining cases of FTD. In 2011, abnormal expansion of a hexanucleotide repeat in the gene C9orf72 was found to be the most common genetic cause of both FTD and ALS. All common FTD-causing genes have seemingly now been discovered and the main pathological proteins identified. In this Review, we highlight recent advances in understanding the molecular aspects of FTD, which will provide the basis for improved patient care through the development of more-targeted diagnostic tests and therapies.
Key Points
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All common frontotemporal dementia (FTD)-causing genes and signature proteins have now been discovered
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Regulation of progranulin—one of the proteins affected in FTD—is one potential therapeutic strategy for this disorder
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Expansion of a GGGGCC hexanucleotide repeat in a noncoding region of the C9orf72 gene is the most common genetic cause of FTD and amyotrophic lateral sclerosis (ALS)
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The pathomechanism of C9orf72 mutation may include haploinsufficiency and/or toxic RNA foci
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Most tau/TDP-negative frontotemporal lobar degeneration (FTLD) cases are characterized by inclusions that are immunoreactive for fused in sarcoma (FUS) and the other FET proteins (EWS and TAF15)
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Differential involvement of the FET proteins in ALS with FUS mutations compared with FTLD-FUS implies that different pathomechanisms are involved in each disease
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Change history
09 April 2013
In the version of this article initially published, the alignment of data in Table 1 was incorrect. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
R. Rademakers is funded by NIH grants P50 AG016574, R01 NS065782 and R01 AG026251, the ALS Therapy Alliance and the Consortium for Frontotemporal Dementia. M. Neumann is funded by the Swiss National Science Foundation grants 31003A-132864 and CRSII3 136222, the German Federal Ministry of Education and Research grant 01GI1005B, the Stavros–Niarchos Foundation, the Synapsis Foundation, and the Hans and Ilse Breuer Foundation. I. Mackenzie is funded by the Canadian Institutes of Health Research grants 179009 and 74580 and the Pacific Alzheimer's Research Foundation Center grant C06-01.
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R. Rademakers, M. Neumann and I. R. Mackenzie contributed equally to researching data for the article, discussions of content, writing the article, and to the review and editing of the manuscript before submission.
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R. Rademakers is a patent holder with the Mayo Clinic. The other authors declare no competing interests.
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Rademakers, R., Neumann, M. & Mackenzie, I. Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 8, 423–434 (2012). https://doi.org/10.1038/nrneurol.2012.117
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DOI: https://doi.org/10.1038/nrneurol.2012.117
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