Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Advances in understanding the molecular basis of frontotemporal dementia

A Correction to this article was published on 09 April 2013

This article has been updated

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

  • All common frontotemporal dementia (FTD)-causing genes and signature proteins have now been discovered

  • Regulation of progranulin—one of the proteins affected in FTD—is one potential therapeutic strategy for this disorder

  • 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)

  • The pathomechanism of C9orf72 mutation may include haploinsufficiency and/or toxic RNA foci

  • 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)

  • Differential involvement of the FET proteins in ALS with FUS mutations compared with FTLD-FUS implies that different pathomechanisms are involved in each disease

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes FTD and ALS linked to chromosome 9p.
Figure 2: Distinct pathomechanisms of ALS-FUS and FTLD-FUS.

Similar content being viewed by others

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.

References

  1. Bird, T. et al. Epidemiology and genetics of frontotemporal dementia/Pick's disease. Ann. Neurol. 54 (Suppl. 5), S29–S31 (2003).

    PubMed  Google Scholar 

  2. Feldman, H. et al. A Canadian cohort study of cognitive impairment and related dementias (ACCORD): study methods and baseline results. Neuroepidemiology 22, 265–274 (2003).

    CAS  PubMed  Google Scholar 

  3. [No authors listed] Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J. Neurol. Neurosurg. Psychiatry 57, 416–418 (1994).

  4. McKhann, G. M. et al. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch. Neurol. 58, 1803–1809 (2001).

    CAS  PubMed  Google Scholar 

  5. Neary, D. et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51, 1546–1554 (1998).

    CAS  PubMed  Google Scholar 

  6. Burrell, J. R., Kiernan, M. C., Vucic, S. & Hodges, J. R. Motor neuron dysfunction in frontotemporal dementia. Brain 134, 2582–2594 (2011).

    PubMed  Google Scholar 

  7. Lomen-Hoerth, C., Anderson, T. & Miller, B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59, 1077–1079 (2002).

    PubMed  Google Scholar 

  8. Rohrer, J. D. et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology 73, 1451–1456 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Seelaar, H. et al. Distinct genetic forms of frontotemporal dementia. Neurology 71, 1220–1226 (2008).

    CAS  PubMed  Google Scholar 

  10. Hutton, M. et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).

    CAS  PubMed  Google Scholar 

  11. Poorkaj, P. et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 43, 815–825 (1998).

    CAS  PubMed  Google Scholar 

  12. Spillantini, M. G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl Acad. Sci. USA 95, 7737–7741 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Alzheimer Disease & Frontotemporal Dementia Mutation Database [online], (2012).

  14. Rademakers, R., Cruts, M. & van Broeckhoven, C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum. Mutat. 24, 277–295 (2004).

    CAS  PubMed  Google Scholar 

  15. Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).

    CAS  PubMed  Google Scholar 

  16. Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006).

    CAS  PubMed  Google Scholar 

  17. Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381 (2004).

    CAS  PubMed  Google Scholar 

  18. Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat. Genet. 37, 806–808 (2005).

    CAS  PubMed  Google Scholar 

  19. Boxer, A. L. et al. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J. Neurol. Neurosurg. Psychiatr. 82, 196–203 (2011).

    Google Scholar 

  20. Gijselinck, I. et al. Identification of 2 loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch. Neurol. 67, 606–616 (2010).

    PubMed  Google Scholar 

  21. Le Ber, I. et al. Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease. Neurology 72, 1669–1676 (2009).

    CAS  PubMed  Google Scholar 

  22. Luty, A. A. et al. Pedigree with frontotemporal lobar degeneration—motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol. 8, 32 (2008).

    PubMed  PubMed Central  Google Scholar 

  23. Momeni, P. et al. Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS–FTD. BMC Neurol. 6, 44 (2006).

    PubMed  PubMed Central  Google Scholar 

  24. Morita, M. et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66, 839–844 (2006).

    CAS  PubMed  Google Scholar 

  25. Pearson, J. P. et al. Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J. Neurol. 258, 647–655 (2011).

    PubMed  Google Scholar 

  26. Valdmanis, P. N. et al. Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch. Neurol. 64, 240–245 (2007).

    PubMed  Google Scholar 

  27. Vance, C. et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 129, 868–876 (2006).

    PubMed  Google Scholar 

  28. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS–FTD. Neuron 72, 257–268 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cairns, N. J. et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 114, 5–22 (2007).

    PubMed  PubMed Central  Google Scholar 

  31. Mackenzie, I. R. et al. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol. 117, 15–18 (2009).

    PubMed  Google Scholar 

  32. Mackenzie, I. R. et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 119, 1–4 (2010).

    PubMed  Google Scholar 

  33. Lipton, A. M., White, C. L. 3rd & Bigio, E. H. Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol. 108, 379–385 (2004).

    PubMed  Google Scholar 

  34. Mackenzie, I. R. et al. Dementia lacking distinctive histology (DLDH) revisited. Acta Neuropathol. 112, 551–559 (2006).

    PubMed  Google Scholar 

  35. Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602–611 (2006).

    CAS  PubMed  Google Scholar 

  36. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).

    CAS  PubMed  Google Scholar 

  37. Kwiatkowski, T. J. Jr et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009).

    CAS  PubMed  Google Scholar 

  38. Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Munoz, D. G. et al. FUS pathology in basophilic inclusion body disease. Acta Neuropathol. 118, 617–627 (2009).

    CAS  PubMed  Google Scholar 

  40. Neumann, M. et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132, 2922–2931 (2009).

    PubMed  PubMed Central  Google Scholar 

  41. Neumann, M. et al. Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol. 118, 605–616 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Neumann, M. et al. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 134, 2595–2609 (2011).

    PubMed  PubMed Central  Google Scholar 

  43. Gijselinck, I., Van Broeckhoven, C. & Cruts, M. Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum. Mutat. 29, 1373–1386 (2008).

    CAS  PubMed  Google Scholar 

  44. Bateman, A. & Bennett, H. P. The granulin gene family: from cancer to dementia. Bioessays 31, 1245–1254 (2009).

    CAS  PubMed  Google Scholar 

  45. Finch, N. et al. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 132, 583–591 (2009).

    PubMed  PubMed Central  Google Scholar 

  46. Ghidoni, R., Benussi, L., Glionna, M., Franzoni, M. & Binetti, G. Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 71, 1235–1239 (2008).

    CAS  PubMed  Google Scholar 

  47. Sleegers, K. et al. Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann. Neurol. 65, 603–609 (2009).

    CAS  PubMed  Google Scholar 

  48. Beck, J. et al. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain 131, 706–720 (2008).

    PubMed  Google Scholar 

  49. Gass, J. et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum. Mol. Genet. 15, 2988–3001 (2006).

    CAS  PubMed  Google Scholar 

  50. Le Ber, I. et al. Progranulin null mutations in both sporadic and familial frontotemporal dementia. Human. Mut. 28, 846–855 (2007).

    CAS  Google Scholar 

  51. Moreno, F. et al. “Frontotemporoparietal” dementia: clinical phenotype associated with the c.709-1G>A PGRN mutation. Neurology 73, 1367–1374 (2009).

    CAS  PubMed  Google Scholar 

  52. Snowden, J. S. et al. Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia. Brain 129, 3091–3102 (2006).

    CAS  PubMed  Google Scholar 

  53. Masellis, M. et al. Novel splicing mutation in the progranulin gene causing familial corticobasal syndrome. Brain 129, 3115–3123 (2006).

    PubMed  Google Scholar 

  54. Cruts, M. & Van Broeckhoven, C. Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet. 24, 186–194 (2008).

    CAS  PubMed  Google Scholar 

  55. Van Deerlin, V. M. et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat. Genet. 42, 234–239 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cruchaga, C. et al. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch. Neurol. 68, 581–586 (2011).

    PubMed  PubMed Central  Google Scholar 

  57. Finch, N. et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 76, 467–474 (2011).

    CAS  PubMed  Google Scholar 

  58. van der Zee, J. et al. TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain 134, 808–815 (2011).

    PubMed  PubMed Central  Google Scholar 

  59. Jiao, J., Herl, L. D., Farese, R. V. & Gao, F. B. MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia. PLoS ONE 5, e10551 (2010).

    PubMed  PubMed Central  Google Scholar 

  60. Wang, W. X. et al. miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am. J. Pathol. 177, 334–345 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Rademakers, R. et al. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum. Mol. Genet. 17, 3631–3642 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Brouwers, N. et al. Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 71, 656–664 (2008).

    CAS  PubMed  Google Scholar 

  63. Lee, M. J., Chen, T. F., Cheng, T. W. & Chiu, M. J. rs5848 variant of progranulin gene is a risk of Alzheimer's disease in the Taiwanese population. Neurodegener. Dis. 8, 216–220 (2011).

    CAS  PubMed  Google Scholar 

  64. Viswanathan, J. et al. An association study between granulin gene polymorphisms and Alzheimer's disease in Finnish population. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 747–750 (2009).

    CAS  PubMed  Google Scholar 

  65. Cenik, B. et al. Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J. Biol. Chem. 286, 16101–16108 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Capell, A. et al. Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. J. Neurosci. 31, 1885–1894 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Gao, X. et al. Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3β. Protein Cell 1, 552–562 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ryan, C. L. et al. Progranulin is expressed within motor neurons and promotes neuronal cell survival. BMC Neurosci. 10, 130 (2009).

    PubMed  PubMed Central  Google Scholar 

  69. Tapia, L. et al. Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses. J. Neurosci. 31, 11126–11132 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Van Damme, P. et al. Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J. Cell. Biol. 181, 37–41 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kleinberger, G. et al. Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J. Neurochem. 115, 735–747 (2010).

    CAS  PubMed  Google Scholar 

  72. Nedachi, T., Kawai, T., Matsuwaki, T., Yamanouchi, K. & Nishihara, M. Progranulin enhances neural progenitor cell proliferation through glycogen synthase kinase 3β phosphorylation. Neuroscience 185, 106–115 (2011).

    CAS  PubMed  Google Scholar 

  73. Rosen, E. Y. et al. Functional genomic analyses identify pathways dysregulated by progranulin deficiency, implicating Wnt signaling. Neuron 71, 1030–1042 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu, J. et al. Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol. Aging 32, 2326.e5–2326.e16 (2011).

    CAS  Google Scholar 

  75. Guo, A., Tapia, L., Bamji, S. X., Cynader, M. S. & Jia, W. Progranulin deficiency leads to enhanced cell vulnerability and TDP-43 translocation in primary neuronal cultures. Brain Res. 1366, 1–8 (2010).

    CAS  PubMed  Google Scholar 

  76. Carrasquillo, M. M. et al. Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma. Am. J. Hum. Genet. 87, 890–897 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Hu, F. et al. Sortilin-mediated endocytosis determines levels of the frontotemporal dementia protein, progranulin. Neuron 68, 654–667 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Tang, W. et al. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332, 478–484 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Boeve, B. F. et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135, 765–783 (2012).

    PubMed  PubMed Central  Google Scholar 

  80. Brettschneider, J. et al. Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. 123, 825–839 (2012).

    PubMed  PubMed Central  Google Scholar 

  81. Byrne, S. et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 11, 232–240 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Chio, A. et al. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain 135, 784–793 (2012).

    PubMed  PubMed Central  Google Scholar 

  83. Cooper-Knock, J. et al. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain 135, 751–764 (2012).

    PubMed  PubMed Central  Google Scholar 

  84. Floris, G. et al. Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype? J. Neurol. http://dx.doi.org/10.1007/s00415-012-6444-3.

  85. Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders–Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 11, 54–65 (2012).

    CAS  PubMed  Google Scholar 

  86. Hsiung, G. Y. et al. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135, 709–722 (2012).

    PubMed  PubMed Central  Google Scholar 

  87. Kandiah, N. et al. Case report of an Asian patient with FTD–ALS due to C9ORF72 mutation. Can. J. Neurol. Sci. (in press).

  88. Mahoney, C. J. et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135, 736–750 (2012).

    PubMed  PubMed Central  Google Scholar 

  89. Majounie, E. et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323–330 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Mok, K. Y. et al. High frequency of the expanded C9ORF72 hexanucleotide repeat in familial and sporadic Greek ALS patients. Neurobiol. Aging http://dx.doi.org/10.1016/j.neurobiolaging.2012.02.021.

  91. Murray, M. E. et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 122, 673–690 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sabatelli, M. et al. C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population. Neurobiol. Aging http://dx.doi.org/10.1016/j.neurobiolaging.2012.02.011.

  93. Simon-Sanchez, J. et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135, 723–735 (2012).

    PubMed  Google Scholar 

  94. Snowden, J. S. et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135, 693–708 (2012).

    PubMed  PubMed Central  Google Scholar 

  95. Stewart, H. et al. Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol. 123, 409–417 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Mok, K. et al. Chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol. Aging 33, 209.e3–209.e8 (2012).

    CAS  Google Scholar 

  97. Rademakers, R. C9orf72 repeat expansions in patients with ALS and FTD. Lancet Neurol. 11, 297–298 (2012).

    PubMed  PubMed Central  Google Scholar 

  98. Whitwell, J. L. et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 135, 794–806 (2012).

    PubMed  PubMed Central  Google Scholar 

  99. Al-Sarraj, S. et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 122, 691–702 (2011).

    CAS  PubMed  Google Scholar 

  100. Troakes, C. et al. An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology http://dx.doi.org/10.1111/j.1440-1789.2011.01286.x.

  101. Lavedan, C. et al. Myotonic dystrophy: size- and sex-dependent dynamics of CTG meiotic instability, and somatic mosaicism. Am. J. Hum. Genet. 52, 875–883 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Matsuura, T. et al. Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10. Am. J. Hum. Genet. 74, 1216–1224 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Moseley, M. L. et al. SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Hum. Mol. Genet. 9, 2125–2130 (2000).

    CAS  PubMed  Google Scholar 

  104. Renoux, A. J. & Todd, P. K. Neurodegeneration the RNA way. Prog. Neurobiol. 97, 173–189 (2011).

    PubMed  PubMed Central  Google Scholar 

  105. Rademakers, R. et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200–205 (2012).

    CAS  Google Scholar 

  106. Kabashi, E. et al. Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum. Mol. Genet. 19, 671–683 (2010).

    CAS  PubMed  Google Scholar 

  107. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Buratti, E. & Baralle, F. E. The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation. RNA Biol. 7, 420–429 (2010).

    CAS  PubMed  Google Scholar 

  110. Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat. Neurosci. 14, 459–468 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat. Neurosci. 14, 452–458 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Van Deerlin, V. M. et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 7, 409–416 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kovacs, G. G. et al. TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov. Disord. 24, 1843–1847 (2009).

    PubMed  Google Scholar 

  114. Neumann, M. et al. TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J. Neuropathol. Exp. Neurol. 66, 152–157 (2007).

    PubMed  Google Scholar 

  115. Cairns, N. J. et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am. J. Pathol. 171, 227–240 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Mackenzie, I. R. et al. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol. 112, 539–549 (2006).

    PubMed  PubMed Central  Google Scholar 

  117. Mackenzie, I. R. et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 122, 111–113 (2011).

    PubMed  PubMed Central  Google Scholar 

  118. Sampathu, D. M. et al. Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am. J. Pathol. 169, 1343–1352 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Hasegawa, M. et al. Molecular dissection of TDP-43 proteinopathies. J. Mol. Neurosci. 45, 480–485 (2011).

    CAS  PubMed  Google Scholar 

  120. Lee, E. B., Lee, V. M. & Trojanowski, J. Q. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat. Rev. Neurosci. 13, 38–50 (2012).

    CAS  Google Scholar 

  121. Mackenzie, I. R., Rademakers, R. & Neumann, M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995–1007 (2010).

    CAS  PubMed  Google Scholar 

  122. Da Cruz, S. & Cleveland, D. W. Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr. Opin. Neurobiol. 21, 904–919 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Tan, A. Y. & Manley, J. L. The TET family of proteins: functions and roles in disease. J. Mol. Cell Biol. 1, 82–92 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Hoell, J. I. et al. RNA targets of wild-type and mutant FET family proteins. Nat. Struct. Mol. Biol. 18, 1428–1431 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Urwin, H. et al. FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol. 120, 33–41 (2010).

    PubMed  PubMed Central  Google Scholar 

  126. Mackenzie, I. R. et al. Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol. 122, 87–98 (2011).

    PubMed  PubMed Central  Google Scholar 

  127. Mackenzie, I. R. et al. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol. 121, 207–218 (2011).

    PubMed  Google Scholar 

  128. Couthouis, J. et al. A yeast functional screen predicts new candidate ALS disease genes. Proc. Natl Acad. Sci. USA 108, 20881–20890 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Couthouis, J. et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. http://dx.doi.org/10.1093/hmg/dds116.

  130. Ticozzi, N. et al. Mutational analysis reveals the FUS homolog TAF15 as a candidate gene for familial amyotrophic lateral sclerosis. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 156, 285–290 (2011).

    CAS  Google Scholar 

  131. Dormann, D. et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 29, 2841–2857 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Ito, D., Seki, M., Tsunoda, Y., Uchiyama, H. & Suzuki, N. Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann. Neurol. 69, 152–162 (2010).

    PubMed  Google Scholar 

  133. Belyanskaya, L. L., Delattre, O. & Gehring, H. Expression and subcellular localization of Ewing sarcoma (EWS) protein is affected by the methylation process. Exp. Cell Res. 288, 374–381 (2003).

    CAS  PubMed  Google Scholar 

  134. Jobert, L., Argentini, M. & Tora, L. PRMT1 mediated methylation of TAF15 is required for its positive gene regulatory function. Exp. Cell Res. 315, 1273–1286 (2009).

    CAS  PubMed  Google Scholar 

  135. Rappsilber, J., Friesen, W. J., Paushkin, S., Dreyfuss, G. & Mann, M. Detection of arginine dimethylated peptides by parallel precursor ion scanning mass spectrometry in positive ion mode. Anal. Chem. 75, 3107–3114 (2003).

    CAS  PubMed  Google Scholar 

  136. Fronz, K. et al. Arginine methylation of the nuclear poly(A) binding protein weakens the interaction with its nuclear import receptor, transportin. J. Biol. Chem. 286, 32986–32994 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Deloulme, J. C., Prichard, L., Delattre, O. & Storm, D. R. The prooncoprotein EWS binds calmodulin and is phosphorylated by protein kinase C through an IQ domain. J. Biol. Chem. 272, 27369–27377 (1997).

    CAS  PubMed  Google Scholar 

  138. Perrotti, D. et al. TLS/FUS, a pro-oncogene involved in multiple chromosomal translocations, is a novel regulator of BCR/ABL-mediated leukemogenesis. EMBO J. 17, 4442–4455 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Leemann-Zakaryan, R. P., Pahlich, S., Grossenbacher, D. & Gehring, H. Tyrosine phosphorylation in the C-terminal nuclear localization and retention signal (C-NLS) of the EWS protein. Sarcoma 2011, 218483 (2011).

    PubMed  PubMed Central  Google Scholar 

  140. Page, T. et al. FUS immunogold labeling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy. J. Mol. Neurosci. 45, 409–421 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Lanson, N. A. Jr & Pandey, U. B. FUS-related proteinopathies: lessons from animal models. Brain Res. http://dx.doi.org/10.1016/j.brainres.2012.01.039.

  142. Josephs, K. A. et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol. 122, 137–153 (2011).

    PubMed  PubMed Central  Google Scholar 

  143. Rohrer, J. D. & Warren, J. D. Phenotypic signatures of genetic frontotemporal dementia. Curr. Opin. Neurol. 24, 542–549 (2011).

    PubMed  Google Scholar 

  144. Hu, W. T., Trojanowski, J. Q. & Shaw, L. M. Biomarkers in frontotemporal lobar degenerations--progress and challenges. Prog. Neurobiol. 95, 636–648 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Noto, Y. et al. Elevated CSF TDP-43 levels in amyotrophic lateral sclerosis: specificity, sensitivity, and a possible prognostic value. Amyotroph. Lateral Scler. 12, 140–143 (2011).

    CAS  PubMed  Google Scholar 

  146. Time is ripe for clinical trials in frontotemporal degeneration. Alzheimer Research Forum [online], (2011).

  147. Pick, A. Über die Beziehungen der senilen Hirnatrophie zur Aphasie [German]. Prager medicinische Wochenschrift 17, 165–167 (1892).

    Google Scholar 

  148. Alzheimer, A. Über eigenartige Krankheitsfäelle des späeteren Alters [German]. Z. Gesamte Neurol. Psychiatrie 4, 356–385 (1911).

    Google Scholar 

  149. Rebeiz, J. J., Kolodny, E. H. & Richardson, E. P. Jr. Corticodentatonigral degeneration with neuronal achromasia. Arch. Neurol. 18, 20–33 (1968).

    CAS  PubMed  Google Scholar 

  150. Steele, J. C., Richardson, J. C. & Olszewski, J. Progressive supranuclear palsy. A heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch. Neurol. 10, 333–359 (1964).

    CAS  PubMed  Google Scholar 

  151. Constantinidis, J., Richard, J. & Tissot, R. Pick's disease. Histological and clinical correlations. Eur. Neurol. 11, 208–217 (1974).

    CAS  PubMed  Google Scholar 

  152. Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001).

    CAS  PubMed  Google Scholar 

  153. Knopman, D. S., Mastri, A. R., Frey, W. H. 2nd, Sung, J. H. & Rustan, T. Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia. Neurology 40, 251–256 (1990).

    CAS  PubMed  Google Scholar 

  154. Jackson, M., Lennox, G. & Lowe, J. Motor neurone disease-inclusion dementia. Neurodegeneration 5, 339–350 (1996).

    CAS  PubMed  Google Scholar 

  155. Mackenzie, I. R., Foti, D., Woulfe, J. & Hurwitz, T. A. Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 131, 1282–1293 (2008).

    PubMed  Google Scholar 

  156. Roeber, S., Mackenzie, I. R., Kretzschmar, H. A. & Neumann, M. TDP-43-negative FTLD-U is a significant new clinico–pathological subtype of FTLD. Acta Neuropathol. 116, 147–157 (2008).

    CAS  PubMed  Google Scholar 

  157. Laaksovirta, H. et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol. 9, 978–985 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Shatunov, A. et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol. 9, 986–994 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. van Es, M. A. et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat. Genet. 41, 1083–1087 (2009).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Ian R. Mackenzie.

Ethics declarations

Competing interests

R. Rademakers is a patent holder with the Mayo Clinic. The other authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2012.117

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing