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Section 4 - Pathology and pathophysiology

Published online by Cambridge University Press:  05 May 2016

Edited by
Bradford C. Dickerson
Bradford C. Dickerson
Affiliation:
Department of Neurology, Massachusetts General Hospital
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Hodges' Frontotemporal Dementia , pp. 165 - 210
Publisher: Cambridge University Press
Print publication year: 2016

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References

References

Rademakers, R, Neumann, M, Mackenzie, IR. Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 2012;8:423–34.CrossRefGoogle ScholarPubMed
Mackenzie, IR, Neumann, M, Bigio, EH, et al. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 2009;117:15–18.Google Scholar
Mackenzie, IR, Neumann, M, Bigio, EH, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 2010;119:1–4.Google Scholar
Weingarten, MD, Lockwood, AH, Hwo, SY, et al. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 1975;72:1858–62.Google Scholar
Goedert, M, Spillantini, MG, Jakes, R, et al. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989;3:519–26.CrossRefGoogle ScholarPubMed
Spillantini, MG, Goedert, M. Tau pathology and neurodegeneration. Lancet Neurol 2013;12:609–22.Google Scholar
Lee, G, Leugers, CJ. Tau and tauopathies. Prog Mol Biol Transl Sci 2012;107:263–93.Google Scholar
Iqbal, K, Liu, F, Gong, CX, et al. Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 2009;118:53–69.CrossRefGoogle ScholarPubMed
Noble, W, Hanger, DP, Miller, CC, et al. The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 2013;4:83.CrossRefGoogle ScholarPubMed
van Swieten, J, Spillantini, MG. Hereditary frontotemporal dementia caused by tau gene mutations. Brain Pathol 2007;17:63–73.Google Scholar
Dickson, DW, Rademakers, R, Hutton, ML. Progressive supranuclear palsy: pathology and genetics. Brain Pathol 2007;17:74–82.CrossRefGoogle ScholarPubMed
Myers, AJ, Pittman, AM, Zhao, AS, et al. The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis 2007;25:561–70.Google Scholar
Kovacs, GG, Rozemuller, AJ, van Swieten, JC, et al. Neuropathology of the hippocampus in FTLD-tau with Pick bodies: a study of the BrainNet Europe Consortium. Neuropathol Appl Neurobiol 2013;39:166–78.Google Scholar
Dickson, DW, Ahmed, Z, Algom, AA, et al. Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol 2010;23:394–400.Google Scholar
Dickson, DW. Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol 1999;246 Suppl 2:116–15.Google Scholar
Kouri, N, Whitwell, JL, Josephs, KA, et al. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011;7:263–72.CrossRefGoogle Scholar
Ahmed, Z, Bigio, EH, Budka, H, et al. Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 2013;126:537–44.CrossRefGoogle ScholarPubMed
Ghetti, B, Wszolek, ZK, Boeve, BF, et al. Frontotemporal dementia and parkinsonism linked to chromosome 17. In: Dickson, DW, Weller, RO, eds. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. Chichester, UK: Blackwell Publishing Ltd.; 2011; 110–34.Google Scholar
Miki, Y, Mori, F, Hori, E, et al. Hippocampal sclerosis with four-repeat tau-positive round inclusions in the dentate gyrus: a new type of four-repeat tauopathy. Acta Neuropathol 2009;117:713–18.CrossRefGoogle ScholarPubMed
Kovacs, GG, Milenkovic, I, Wohrer, A, et al. Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol 2013;126:365–84.CrossRefGoogle Scholar
Tolnay, M, Probst, A. Argyrophilic grain disease. Handb Clin Neurol 2008;89:553–63.Google Scholar
Saito, Y, Ruberu, NN, Sawabe, M, et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 2004;63:911–18.Google Scholar
Jellinger, KA, Attems, J. Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathol 2007;113:107–17.Google Scholar
Frank, S, Clavaguera, F, Tolnay, M. Tauopathy models and human neuropathology: similarities and differences. Acta Neuropathol 2008;115:39–53.Google Scholar
Clavaguera, F, Akatsu, H, Fraser, G, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci USA 2013;110:9535–40.CrossRefGoogle ScholarPubMed
Halliday, G, Bigio, EH, Cairns, NJ, et al. Mechanisms of disease in frontotemporal lobar degeneration: gain of function versus loss of function effects. Acta Neuropathol 2012;124:373–82.Google Scholar
Neumann, M, Sampathu, DM, Kwong, LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314:130–3.Google Scholar
Buratti, E, Baralle, FE. The multiple roles of TDP-43 in pre-mRNA processing and gene expression regulation. RNA Biol 2010;7:420–9.CrossRefGoogle ScholarPubMed
Mackenzie, IR, Rademakers, R, Neumann, M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 2010;9:995–1007.Google Scholar
Neumann, M, Kwong, LK, Lee, EB, et al. Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 2009;117:137–49.CrossRefGoogle ScholarPubMed
Igaz, LM, Kwong, LK, Xu, Y, et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol 2008;173:182–94.Google Scholar
Sampathu, DM, Neumann, M, Kwong, LK, et al. Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 2006;169:1343–52.Google Scholar
Mackenzie, IR, Baborie, A, Pickering-Brown, S, et al. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 2006;112:539–49.Google Scholar
Cairns, NJ, Neumann, M, Bigio, EH, et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 2007;171:227–40.CrossRefGoogle ScholarPubMed
Neumann, M, Mackenzie, IR, Cairns, NJ, et al. TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 2007;66:152–7.Google Scholar
Mackenzie, IR, Neumann, M, Baborie, A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011;122:111–13.Google Scholar
Baker, M, Mackenzie, IR, Pickering-Brown, SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–19.Google Scholar
Cruts, M, Gijselinck, I, van der Zee, J, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920–4.Google Scholar
Mackenzie, IR, Baker, M, Pickering-Brown, S, et al. The neuropathology of frontotemporal lobar degeneration caused by mutations in the progranulin gene. Brain 2006;129:3081–90.Google Scholar
DeJesus-Hernandez, M, Mackenzie, IR, Boeve, BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245–56.CrossRefGoogle ScholarPubMed
Renton, AE, Majounie, E, Waite, A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257–68.Google Scholar
Hsiung, GY, DeJesus-Hernandez, M, Feldman, HH, et al. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 2012;135:709–22.Google Scholar
Mori, K, Weng, SM, Arzberger, T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339:1335–8.Google Scholar
Ash, PE, Bieniek, KF, Gendron, TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013;77:639–46.CrossRefGoogle ScholarPubMed
Mackenzie, IR, Arzberger, T, Kremmer, E, et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 2013;126:859–79.Google Scholar
Kimonis, VE, Fulchiero, E, Vesa, J, et al. VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder. Biochim Biophys Acta 2008;1782:744–8.Google Scholar
Borroni, B, Bonvicini, C, Alberici, A, et al. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat 2009;30:E974–83.Google Scholar
Benajiba, L, Le Ber, I, Camuzat, A, et al. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol 2009;65:470–3.Google Scholar
Kovacs, GG, Murrell, JR, Horvath, S, et al. TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov Disord 2009;24:1843–7.CrossRefGoogle ScholarPubMed
Lee, EB, Lee, VM, Trojanowski, JQ. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 2012;13:38–50.CrossRefGoogle ScholarPubMed
Da Cruz, S, Cleveland, DW. Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol 2011;21:904–19.Google Scholar
Wu, LS, Cheng, WC, Shen, CK. Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem 2012;287:27335–44.Google Scholar
Neumann, M, Rademakers, R, Roeber, S, et al. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 2009;132:2922–31.Google Scholar
Kwiatkowski, TJ Jr., Bosco, DA, Leclerc, AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009;323:1205–8.Google Scholar
Vance, C, Rogelj, B, Hortobagyi, T, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 2009;323:1208–11.Google Scholar
Neumann, M, Roeber, S, Kretzschmar, HA, et al. Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 2009;118:605–16.CrossRefGoogle ScholarPubMed
Munoz, DG, Neumann, M, Kusaka, H, et al. FUS pathology in basophilic inclusion body disease. Acta Neuropathol 2009;118:617–27.Google Scholar
Neumann, M, Bentmann, E, Dormann, D, et al. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 2011;134:2595–609.Google Scholar
Neumann, M, Valori, CF, Ansorge, O, et al. Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations. Acta Neuropathol 2012;124:705–16.Google Scholar
Tan, AY, Manley, JL. The TET family of proteins: functions and roles in disease. J Mol Cell Biol 2009;1:82–92.Google Scholar
Kovar, H. Jekyll, Dr. and Mr. Hyde: the two faces of the FUS/EWS/TAF15 protein family. Sarcoma 2011;2011:837474.Google Scholar
Fujii, R, Takumi, T. TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J Cell Sci 2005;118:5755–65.Google Scholar
Dormann, D, Madl, T, Valori, CF, et al. Arginine methylation next to the PY-NLS modulates transportin binding and nuclear import of FUS. EMBO J 2012;31:4258–75.Google Scholar
Cairns, NJ, Grossman, M, Arnold, SE, et al. Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease. Neurology 2004;63:1376–84.Google Scholar
Mackenzie, IR, Foti, D, Woulfe, J, et al. Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions. Brain 2008;131:1282–93.Google Scholar
Mackenzie, IR, Munoz, DG, Kusaka, H, et al. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 2011;121:207–18.Google Scholar
Mackenzie, IR, Feldman, H. Neurofilament inclusion body disease with early onset frontotemporal dementia and primary lateral sclerosis. Clin Neuropathol 2004;23:183–93.Google Scholar
Dormann, D, Rodde, R, Edbauer, D, et al. ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J 2010;29:2841–57.Google Scholar
Ravenscroft, TA, Baker, MC, Rutherford, NJ, et al. Mutations in protein N-arginine methyltransferases are not the cause of FTLD-FUS. Neurobiol Aging 2013;34:2235.e11–13.Google Scholar
Holm, IE, Englund, E, Mackenzie, IR, et al. A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3. J Neuropathol Exp Neurol 2007;66:884–91.Google Scholar
Holm, IE, Isaacs, AM, Mackenzie, IR. Absence of FUS-immunoreactive pathology in frontotemporal dementia linked to chromosome 3 (FTD-3) caused by mutation in the CHMP2B gene. Acta Neuropathol 2009;118:719–20.Google Scholar
Wider, C, Van Gerpen, JA, DeArmond, S, et al. Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD): a single entity? Neurology 2009;72:1953–9.Google Scholar
Forman, MS, Farmer, J, Johnson, JK, et al. Frontotemporal dementia: clinicopathological correlations. Ann Neurol 2006;59:952–62.Google Scholar
Munoz, DG, Woulfe, J, Kertesz, A. Argyrophilic thorny astrocyte clusters in association with Alzheimer's disease pathology in possible primary progressive aphasia. Acta Neuropathol 2007;114:347–57.Google Scholar
Josephs, KA, Hodges, JR, Snowden, JS, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol 2011;122:137–53.Google Scholar

References

Sieben, A, Van Langenhove, T, Engelborghs, S, Martin, JJ, Boon, P, Cras, P, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 2012;124(3):353–72.Google Scholar
Mackenzie, IR, Neumann, M, Bigio, EH, Cairns, NJ, Alafuzoff, I, Kril, J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 2010;119(1):1–4.Google Scholar
Neumann, M, Sampathu, DM, Kwong, LK, Truax, AC, Micsenyi, MC, Chou, TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314(5796):130–3.Google Scholar
Arai, T, Hasegawa, M, Akiyama, H, Ikeda, K, Nonaka, T, Mori, H, 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 2006;351(3):602–11.Google Scholar
Mackenzie, IR, Neumann, M, Baborie, A, Sampathu, DM, Du Plessis, D, Jaros, E, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011;122(1):111–13.Google Scholar
Neary, D, Snowden, J, Mann, D. Frontotemporal dementia. Lancet Neurol 2005;4(11):771–80.Google Scholar
Cruts, M, Theuns, J, Van Broeckhoven, C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 2012;33(9):1340–4.Google Scholar
Van Langenhove, T, van der Zee, J, Van Broeckhoven, C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med 2012;44(8):817–28.Google Scholar
Van Deerlin, V, Sleiman, PM, Martinez-Lage, M, Chen-Plotkin, A, Wang, LS, Graff-Radford, NR, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 2010;42(3):234–9.Google Scholar
Foster, NL, Wilhelmsen, K, Sima, AA, Jones, MZ, D'Amato, CJ, Gilman, S, et al. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 1997;41(6):706–15.Google Scholar
Hutton, M, Lendon, CL, Rizzu, P, Baker, M, Froelich, S, Houlden, H, et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393(6686):702–5.CrossRefGoogle ScholarPubMed
D'Souza, I, Schellenberg, GD. Tau exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5′ and 3′ splice sites. J Biol Chem 2002;277(29):26587–99.Google Scholar
Rademakers, R, Cruts, M, Van Broeckhoven, C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 2004;24(4):277–95.Google Scholar
Cruts, M, Van Broeckhoven, C. Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet 2008;24(4):186–94.Google Scholar
Josephs, KA, Hodges, JR, Snowden, JS, Mackenzie, IR, Neumann, M, Mann, DM, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol 2011;122(2):137–53.Google Scholar
Baker, M, Mackenzie, IR, Pickering-Brown, SM, Gass, J, Rademakers, R, Lindholm, C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442(7105):916–19.Google Scholar
Cruts, M, Gijselinck, I, van der Zee, J, Engelborghs, S, Wils, H, Pirici, D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442(7105):920–4.Google Scholar
Kleinberger, G, Capell, A, Haass, C, Van Broeckhoven, C. Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol Neurobiol 2013;47(1):337–60.Google Scholar
Brouwers, N, Sleegers, K, Engelborghs, S, Maurer-Stroh, S, Gijselinck, I, van der Zee, J, et al. Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 2008;71(9):656–64.CrossRefGoogle ScholarPubMed
Sleegers, K, Brouwers, N, Van Broeckhoven, C. Role of progranulin as a biomarker for Alzheimer's disease. Biomark Med 2010;4(1):37–50.Google Scholar
Sleegers, K, Brouwers, N, Maurer-Stroh, S, van Es, MA, Van Damme, P, Van Vught, PW, et al. Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology 2008;71(4):253–9.CrossRefGoogle ScholarPubMed
Rohrer, JD, Warren, JD. Phenotypic signatures of genetic frontotemporal dementia. Curr Opin Neurol 2011;24(6):542–9.Google Scholar
Le Ber, I, Camuzat, A, Hannequin, D, Pasquier, F, Guedj, E, Rovelet-Lecrux, A, et al. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain 2008;131(Pt 3):732–46.Google Scholar
Brouwers, N, Nuytemans, K, van der Zee, J, Gijselinck, I, Engelborghs, S, Theuns, J, et al. Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol 2007;64(10):1436–46.Google Scholar
Chen-Plotkin, AS, Martinez-Lage, M, Sleiman, PM, Hu, W, Greene, R, Wood, EM, et al. Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Arch Neurol 2011;68(4):488–97.Google Scholar
Rademakers, R, Baker, M, Gass, J, Adamson, J, Huey, ED, Momeni, P, et al. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative. Lancet Neurol 2007;6(10):857–68.Google Scholar
Vance, C, Al Chalabi, A, Ruddy, D, Smith, BN, Hu, X, Sreedharan, J, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 2006;129(Pt 4):868–76.Google Scholar
Morita, M, Al Chalabi, A, Andersen, PM, Hosler, B, Sapp, P, Englund, E, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 2006;66(6):839–44.Google Scholar
Laaksovirta, H, Peuralinna, T, Schymick, JC, Scholz, SW, Lai, SL, Myllykangas, L, et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol 2010;9(10):978–85.Google Scholar
DeJesus-Hernandez, M, Mackenzie, IR, Boeve, BF, Boxer, AL, Baker, M, Rutherford, NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72(2):245–56.Google Scholar
Renton, AE, Majounie, E, Waite, A, Simon-Sanchez, J, Rollinson, S, Gibbs, JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72(2):257–68.Google Scholar
Gijselinck, I, Van Langenhove, T, van der Zee, J, Sleegers, K, Philtjens, S, Kleinberger, G, 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 2012;11(1):54–65.Google Scholar
Cruts, M, Gijselinck, I, Van Langenhove, T, van der Zee, J, Van Broeckhoven, C. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci 2013;36(8):450–9.Google Scholar
Majounie, E, Renton, AE, Mok, K, Dopper, EG, Waite, A, Rollinson, S, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 2012;11(4):323–30.Google Scholar
Smith, BN, Newhouse, S, Shatunov, A, Vance, C, Topp, S, Johnson, L, et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet 2013;21(1):102–8.Google Scholar
Beck, J, Poulter, M, Hensman, D, Rohrer, JD, Mahoney, CJ, Adamson, G, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 2013;92(3):345–53.Google Scholar
Abel, O, Powell, JF, Andersen, PM, Al-Chalabi, A. ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat 2012;33(9):1345–51.Google Scholar
Mackenzie, IR, Frick, P, Neumann, M. The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta Neuropathol 2014;127(3):347–57.Google Scholar
Mori, K, Lammich, S, Mackenzie, IR, Forne, I, Zilow, S, Kretzschmar, H, et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol 2013;125(3):413–23.Google Scholar
Mori, K, Weng, SM, Arzberger, T, May, S, Rentzsch, K, Kremmer, E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339(6125):1335–8.Google Scholar
Snowden, JS, Rollinson, S, Thompson, JC, Harris, JM, Stopford, CL, Richardson, AM, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135(Pt 3):693–708.Google Scholar
Murray, ME, DeJesus-Hernandez, M, Rutherford, NJ, Baker, M, Duara, R, Graff-Radford, NR, et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 2011;122(6):673–90.Google Scholar
Van Langenhove, T, van der Zee, J, Gijselinck, I, Engelborghs, S, Vandenberghe, R, Vandenbulcke, M, et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol 2013;70(3):365–73.Google Scholar
Boeve, BF, Boylan, KB, Graff-Radford, NR, DeJesus-Hernandez, M, Knopman, DS, Pedraza, O, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;135(Pt 3):765–83.Google Scholar
Watts, GD, Wymer, J, Kovach, MJ, Mehta, SG, Mumm, S, Darvish, D, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004;36(4):377–81.Google Scholar
Weihl, CC, Pestronk, A, Kimonis, VE. Valosin-containing protein disease: inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia. Neuromuscul Disord 2009;19(5):308–15.CrossRefGoogle ScholarPubMed
Dai, RM, Li, CC. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol 2001;3(8):740–4.Google Scholar
Ju, JS, Weihl, CC. p97/VCP at the intersection of the autophagy and the ubiquitin proteasome system. Autophagy 2010;6(2):283–5.Google Scholar
Schroder, R, Watts, GD, Mehta, SG, Evert, BO, Broich, P, Fliessbach, K, et al. Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Ann Neurol 2005;57(3):457–61.Google Scholar
Weihl, CC. Valosin containing protein associated fronto-temporal lobar degeneration: clinical presentation, pathologic features and pathogenesis. Curr Alzheimer Res 2011;8(3):252–60.Google Scholar
Johnson, JO, Mandrioli, J, Benatar, M, Abramzon, Y, Van Deerlin, VM, Trojanowski, JQ, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 2010;68(5):857–64.Google Scholar
Skibinski, G, Parkinson, NJ, Brown, JM, Chakrabarti, L, Lloyd, SL, Hummerich, H, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 2005;37(8):806–8.Google Scholar
van der Zee, J, Urwin, H, Engelborghs, S, Bruyland, M, Vandenberghe, R, Dermaut, B, et al. CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum Mol Genet 2008;17(2):313–22.Google Scholar
Urwin, H, Authier, A, Nielsen, JE, Metcalf, D, Powell, C, Froud, K, et al. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum Mol Genet 2010;19(11):2228–38.Google Scholar
Cox, LE, Ferraiuolo, L, Goodall, EF, Heath, PR, Higginbottom, A, Mortiboys, H, et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS One 2010;5(3):e9872.Google Scholar
Isaacs, AM, Johannsen, P, Holm, I, Nielsen, JE. Frontotemporal dementia caused by CHMP2B mutations. Curr Alzheimer Res 2011;8(3):246–51.Google Scholar
Borroni, B, Bonvicini, C, Alberici, A, Buratti, E, Agosti, C, Archetti, S, et al. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat 2009;30(11):E974–83.Google Scholar
Kwiatkowski, TJ Jr., Bosco, DA, Leclerc, AL, Tamrazian, E, Vanderburg, CR, Russ, C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009;323(5918):1205–8.Google Scholar
Van Langenhove, T, van der Zee, J, Sleegers, K, Engelborghs, S, Vandenberghe, R, Gijselinck, I, et al. Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 2010;74(5):366–71.Google Scholar
Mackenzie, IR, Munoz, DG, Kusaka, H, Yokota, O, Ishihara, K, Roeber, S, et al. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 2011;121(2):207–18.CrossRefGoogle ScholarPubMed
Lashley, T, Rohrer, JD, Bandopadhyay, R, Fry, C, Ahmed, Z, Isaacs, AM, et al. A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain 2011;134(Pt 9):2548–64.Google Scholar
van der Zee, J, Van Broeckhoven, C. TMEM106B a novel risk factor for frontotemporal lobar degeneration. J Mol Neurosci 2011;45(3):516–21.Google Scholar
van der Zee, J, Van Langenhove, T, Kleinberger, G, Sleegers, K, Engelborghs, S, Vandenberghe, R, et al. TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain 2011;134(3):808–15.CrossRefGoogle Scholar
Cruchaga, C, Graff, C, Chiang, HH, Wang, J, Hinrichs, AL, Spiegel, N, et al. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol 2011;68(5):581–6.Google Scholar
Premi, E, Formenti, A, Gazzina, S, Archetti, S, Gasparotti, R, Padovani, A, et al. Effect of TMEM106B polymorphism on functional network connectivity in asymptomatic GRN mutation carriers. JAMA Neurol 2014;71(2):216–21.Google Scholar
Vass, R, Ashbridge, E, Geser, F, Hu, WT, Grossman, M, Clay-Falcone, D, et al. Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol 2011;121(3):373–80.Google Scholar
van Blitterswijk, M, Mullen, B, Nicholson, AM, Bieniek, KF, Heckman, MG, Baker, MC, et al. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 2014;127(3):397–406.Google Scholar
Gallagher, MD, Suh, E, Grossman, M, Elman, L, McCluskey, L, van Swieten, JC, et al. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 2014;127(3):407–18.Google Scholar
Lang, CM, Fellerer, K, Schwenk, BM, Kuhn, PH, Kremmer, E, Edbauer, D, et al. Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem 2012;287(23):19355–65.Google Scholar
Brady, OA, Zheng, Y, Murphy, K, Huang, M, Hu, F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 2013;22(4):685–95.Google Scholar
Schwenk, BM, Lang, CM, Hogl, S, Tahirovic, S, Orozco, D, Rentzsch, K, et al. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J 2014;33(5):450–67.Google Scholar
Cruts, M, Rademakers, R, Gijselinck, I, van der Zee, J, Dermaut, B, De Pooter, T, et al. Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low copy repeats in the tau region. Hum Mol Genet 2005;14(13):1753–62.Google Scholar
Rademakers, R, Melquist, S, Cruts, M, Theuns, J, Del Favero, J, Poorkaj, P, et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 2005;14(21):3281–92.Google Scholar
Hoglinger, GU, Melhem, NM, Dickson, DW, Sleiman, PM, Wang, LS, Klei, L, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011;43(7):699–705.CrossRefGoogle ScholarPubMed
Rademakers, R, Eriksen, JL, Baker, M, Robinson, T, Ahmed, Z, Lincoln, SJ, 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 2008;17(23):3631–42.Google Scholar
Galimberti, D, Fenoglio, C, Cortini, F, Serpente, M, Venturelli, E, Villa, C, et al. GRN variability contributes to sporadic frontotemporal lobar degeneration. J Alzheimers Dis 2010;19(1):171–7.Google Scholar
Banzhaf-Strathmann, J, Claus, R, Mucke, O, Rentzsch, K, van der Zee, J, Engelborghs, S, et al. Promoter DNA methylation regulates progranulin expression and is altered in FTLD. Acta Neuropathol Commun 2013;1(1):16.Google Scholar
van der Zee, J, Gijselinck, I, Dillen, L, Van Langenhove, T, Theuns, J, Engelborghs, S, et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability and intermediate repeats. Hum Mutat 2013;34(2):363–73.Google Scholar
Janssens, J, Van Broeckhoven, C. Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders. Hum Mol Genet 2013;22(R1):R77–7.Google Scholar
Gijselinck, I, Van Broeckhoven, C, Cruts, M. Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum Mutat 2008;29(12):1373–86.Google Scholar
Cirulli, ET, Lasseigne, BN, Petrovski, S, Sapp, PC, Dion, PA, Leblond, CS, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 2015;347(6229):1436–41.Google Scholar
Freischmidt, A, Wieland, T, Richter, B, Ruf, W, Schaeffer, V, Muller, K, et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 2015;18(5):631–6.Google Scholar
Pottier, C, Bieniek, KF, Finch, N, van de Vorst, M, Baker, M, Perkersen, R, et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol 2015;130(1):77–92.Google Scholar
Gijselinck, I, Van Mossevelde, S, van der Zee, J, Sieben, A, Philtjens, S, Heeman, B, et al. Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. Neurology 2015. In press.Google Scholar

References

DeJesus-Hernandez, M, Mackenzie, IR, Boeve, BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245–56.Google Scholar
Renton, AE, Majounie, E, Waite, A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72:257–68.Google Scholar
Rutherford, NJ, Heckman, MG, DeJesus-Hernandez, M, et al. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging 2012;33:2950.e5–7.Google Scholar
Ciura, S, Lattante, S, Le Ber, I, et al. Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 2013;74(2):180–7.Google Scholar
Xi, Z, Zinman, L, Moreno, D, et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet 2013;92: 981–9.Google Scholar
Belzil, VV, Bauer, PO, Prudencio, M, et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol 2013;126:895–905.Google Scholar
Haeusler, AR, Donnelly, CJ, Periz, G, et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 2014;507:195–200.Google Scholar
Xu, Z, Poidevin, M, Li, X, et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci USA 2013;110:7778–83.Google Scholar
Gendron, TF, Bieniek, KF, Zhang, YJ, et al. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation in c9FTD/ALS. Acta Neuropathol 2013;126:829–44.Google Scholar
Ash, PE, Bieniek, KF, Gendron, TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013;77:639–46.Google Scholar
Mori, K, Weng, SM, Arzberger, T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339:1335–8.Google Scholar
Lagier-Tourenne, C, Baughn, M, Rigo, F, et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci USA 2013;110:E4530–9.Google Scholar
Lee, YB, Chen, HJ, Peres, JN, et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep 2013;5:1178–86.Google Scholar
van Swieten, J, Spillantini, MG. Hereditary frontotemporal dementia caused by tau gene mutations. Brain Pathol 2007;17:63–73.Google Scholar
Hutton, M, Lendon, CL, Rizzu, P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–5.Google Scholar
Poorkaj, P, Bird, TD, Wijsman, E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998;43:815–25.Google Scholar
Spillantini, MG, Murrell, JR, Goedert, M, et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998;95:7737–41.Google Scholar
Alzheimer Disease & Frontotemporal Dementia Mutation Database. Available from: http://www.molgen.ua.ac.be/FTDMutations.Google Scholar
Alonso Adel, C, Mederlyova, A, Novak, M, et al. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 2004;279:34873–81.Google Scholar
Liu, F, Gong, CX. Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 2008;3:8.Google Scholar
Goedert, M, Jakes, R. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J 1990;9:4225–30.Google Scholar
Brion, JP, Tremp, G, Octave, JN. Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease. Am J Pathol 1999;154:255–70.Google Scholar
Gotz, J, Probst, A, Spillantini, MG, et al. Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform. EMBO J 1995;14:1304–13.Google Scholar
Probst, A, Gotz, J, Wiederhold, KH, et al. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol 2000;99:469–81.Google Scholar
Ishihara, T, Hong, M, Zhang, B, et al. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 1999;24:751–62.Google Scholar
Ishihara, T, Zhang, B, Higuchi, M, et al. Age-dependent induction of congophilic neurofibrillary tau inclusions in tau transgenic mice. Am J Pathol 2001;158: 555–62.Google Scholar
Higuchi, M, Ishihara, T, Zhang, B, et al. Transgenic mouse model of tauopathies with glial pathology and nervous system degeneration. Neuron 2002;35: 433–46.Google Scholar
Lewis, J, McGowan, E, Rockwood, J, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 2000;25:402–5.Google Scholar
Götz, J, Chen, F, Barmettler, R, et al. Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 2001;276:529–34.Google Scholar
SantaCruz, K, Lewis, J, Spires, T, et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 2005;309:476–81.Google Scholar
Allen, B, Ingram, E, Takao, M, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 2002;22:9340–51.Google Scholar
Spires, TL, Orne, JD, SantaCruz, K, et al. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 2006;168:1598–607.Google Scholar
de Calignon, A, Fox, LM, Pitstick, R, et al. Caspase activation precedes and leads to tangles. Nature 2010;464:1201–4.Google Scholar
Andorfer, C, Acker, CM, Kress, Y, et al. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 2005;25:5446–54.Google Scholar
Mocanu, MM, Nissen, A, Eckermann, K, et al. The potential for β-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous tau in inducible mouse models of tauopathy. J Neurosci 2008;28:737–48.Google Scholar
Kuchibhotla, KV, Wegmann, S, Kopeikina, KJ, et al. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci USA 2014;111:510–14.Google Scholar
Rocher, AB, Crimins, JL, Amatrudo, JM, et al. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp Neurol 2010;223:385–93.Google Scholar
Yoshiyama, Y, Higuchi, M, Zhang, B, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007;53:337–51.Google Scholar
Sydow, A, Van der Jeugd, A, Zheng, F, et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic tau mutant. J Neurosci 2011;31:2511–25.Google Scholar
Hoover, BR, Reed, MN, Su, J, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010;68:1067–81.Google Scholar
Yamada, K, Holth, JK, Liao, F, et al. Neuronal activity regulates extracellular tau in vivo. J Exp Med 2014;211:387–93.Google Scholar
Frost, B, Jacks, RL, Diamond, MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 2009;284:12845–52.Google Scholar
Kfoury, N, Holmes, BB, Jiang, H, et al. Trans-cellular propagation of tau aggregation by fibrillar species. J Biol Chem 2012;287:19440–51.Google Scholar
Guo, JL, Lee, VM. Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 2011;286:15317–31.Google Scholar
Wu, JW, Herman, M, Liu, L, et al. Small misfolded tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 2013;288:1856–70.Google Scholar
Clavaguera, F, Bolmont, T, Crowther, RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009;11:909–13.Google Scholar
Liu, L, Drouet, V, Wu, JW, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One 2012;7:e31302.Google Scholar
de Calignon, A, Polydoro, M, Suárez-Calvet, M, et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 2012;73:685–97.Google Scholar
Seeley, WW, Crawford, RK, Zhou, J, et al. Neurodegenerative diseases target large-scale human brain networks. Neuron 2009;62:42–52.Google Scholar
Seeley, WW. Anterior insula degeneration in frontotemporal dementia. Brain Struct Funct 2010;214:465–75.Google Scholar
Rabinovici, GD, Seeley, WW, Kim, EJ, et al. Distinct MRI atrophy patterns in autopsy-proven Alzheimer's disease and frontotemporal lobar degeneration. Am J Alzheimers Dis Other Demen 2007;22:474–88.Google Scholar
Zhou, J, Greicius, MD, Gennatas, ED, et al. Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain 2010;133:1352–67.Google Scholar
Zhou, J, Gennatas, ED, Kramer, JH, et al. Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 2012;73:1216–27.Google Scholar
Mackenzie, IR, Neumann, M, Baborie, A, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011;122:111–13.Google Scholar
Perry, DC, Lehmann, M, Yokoyama, JS, et al. Progranulin mutations as risk factors for Alzheimer disease. JAMA Neurol 2013;70:774–8.Google Scholar
Cenik, B, Sephton, CF, Kutluk Cenik, B, et al. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem 2012;287:32298–306.Google Scholar
Van Damme, P, Van Hoecke, A, Lambrechts, D, et al. Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J Cell Biol 2008;181:37–41.Google Scholar
Gass, J, Lee, WC, Cook, C, et al. Progranulin regulates neuronal outgrowth independent of sortilin. Mol Neurodegener 2012;7:33.Google Scholar
Bateman, A, Bennett, HP. The granulin gene family: from cancer to dementia. Bioessays 2009;31:1245–54.Google Scholar
Tang, W, Lu, Y, Tian, QY, et al. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 2011;332:478–84.Google Scholar
Chen, X, Chang, J, Deng, Q, et al. Progranulin does not bind tumor necrosis factor (TNF) receptors and is not a direct regulator of TNF-dependent signaling or bioactivity in immune or neuronal cells. J Neurosci 2013;33:9202–13.Google Scholar
Kao, AW, Eisenhut, RJ, Martens, LH, et al. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci USA 2011;108:4441–6.Google Scholar
Yin, F, Banerjee, R, Thomas, B, et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med 2010;207:117–28.Google Scholar
Ahmed, Z, Sheng, H, Xu, YF, et al. Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol 2010;177:311–24.Google Scholar
Petkau, TL, Neal, SJ, Milnerwood, A, et al. Synaptic dysfunction in progranulin-deficient mice. Neurobiol Dis 2012;45:711–22.Google Scholar
Filiano, AJ, Martens, LH, Young, AH, et al. Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice. J Neurosci 2013;33:5352–61.Google Scholar
Finch, N, Carrasquillo, MM, Baker, M, et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology 2011;76:467–74.CrossRefGoogle ScholarPubMed
Chen-Plotkin, AS, Unger, TL, Gallagher, MD, et al. TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci 2012;32:11213–27.Google Scholar
Kayasuga, Y, Chiba, S, Suzuki, M, et al. Alteration of behavioural phenotype in mice by targeted disruption of the progranulin gene. Behav Brain Res 2007;185:110–18.Google Scholar
Yin, F, Dumont, M, Banerjee, R, et al. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J 2010;24:4639–47.Google Scholar
Ghoshal, N, Dearborn, JT, Wozniak, DF, et al. Core features of frontotemporal dementia recapitulated in progranulin knockout mice. Neurobiol Dis 2012;45:395–408.Google Scholar
Wils, H, Kleinberger, G, Pereson, S, et al. Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. J Pathol 2012;228:67–76.Google Scholar
Ling, SC, Polymenidou, M, Cleveland, DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 2013;79:416–38.Google Scholar
Li, YR, King, OD, Shorter, J, et al. Stress granules as crucibles of ALS pathogenesis. J Cell Biol 2013;201:361–72.Google Scholar
Lattante, S, Rouleau, GA, Kabashi, E. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum Mutat 2013;34:812–26.Google Scholar
Cushman, M, Johnson, BS, King, OD, et al. Prion-like disorders: blurring the divide between transmissibility and infectivity. J Cell Sci 2010;123:1191–201.Google Scholar
King, OD, Gitler, AD, Shorter, J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res 2012;1462:61–80.Google Scholar
Wu, LS, Cheng, WC, Hou, SC, et al. TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 2010;48:56–62.Google Scholar
Sephton, CF, Good, SK, Atkin, S, et al. TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 2010;285:6826–34.Google Scholar
Kraemer, BC, Schuck, T, Wheeler, JM, et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 2010;119:409–19.Google Scholar
Chiang, P-M, Ling, J, Jeong, YH, et al. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci USA 2010;107:16320–4.Google Scholar
Iguchi, Y, Katsuno, M, Niwa, J, et al. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 2013;136:1371–82.Google Scholar
Wu, LS, Cheng, WC, Shen, CK. Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J Biol Chem 2012;287:27335–44.Google Scholar
Hicks, GG, Singh, N, Nashabi, A, et al. Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nat Genet 2000;24:175–9.Google Scholar
Tsao, W, Jeong, YH, Lin, S, et al. Rodent models of TDP-43: recent advances. Brain Res 2012;1462:26–39.Google Scholar
Roberson, ED. Mouse models of frontotemporal dementia. Ann Neurol 2012;72:837–49.Google Scholar
Ayala, YM, De Conti, L, Avendano-Vazquez, SE, et al. TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J 2011;30:277–88.Google Scholar
Verbeeck, C, Deng, Q, DeJesus-Hernandez, M, et al. Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. Mol Neurodegener 2012;7:53.Google Scholar
Mitchell, JC, McGoldrick, P, Vance, C, et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol 2013;125:273–88.Google Scholar
Qiu, H, Lee, S, Shang, Y, et al. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest 2014;124:981–99.Google Scholar
Watts, GD, Wymer, J, Kovach, MJ, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004;36:377–81.Google Scholar
van der Zee, J, Pirici, D, Van Langenhove, T, et al. Clinical heterogeneity in 3 unrelated families linked to VCP p.Arg159His. Neurology 2009;73:626–32.Google Scholar
Kim, EJ, Park, YE, Kim, DS, et al. Inclusion body myopathy with Paget disease of bone and frontotemporal dementia linked to VCP p.Arg155Cys in a Korean family. Arch Neurol 2011;68:787–96.Google Scholar
Forman, MS, Mackenzie, IR, Cairns, NJ, et al. Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations. J Neuropathol Exp Neurol 2006;65:571–81.Google Scholar
Müller, JM, Deinhardt, K, Rosewell, I, et al. Targeted deletion of p97 (VCP/CDC48) in mouse results in early embryonic lethality. Biochem Biophys Res Commun 2007;354:459–65.Google Scholar
Badadani, M, Nalbandian, A, Watts, GD, et al. VCP associated inclusion body myopathy and Paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease. PLoS One 2010;5:e13183.Google Scholar
Custer, SK, Neumann, M, Lu, H, et al. Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain and bone. Hum Mol Genet 2010;19:1741–55.Google Scholar
Rodriguez-Ortiz, CJ, Hoshino, H, Cheng, D, et al. Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice. Am J Pathol 2013;183:504–15.Google Scholar
Yin, HZ, Nalbandian, A, Hsu, CI, et al. Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice. Cell Death Dis 2012;3:e374.Google Scholar
Llewellyn, KJ, Nalbandian, A, Jung, KM, et al. Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. Hum Mol Genet 2014;23:1333–44.Google Scholar
Gydesen, S, Brown, JM, Brun, A, et al. Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 2002;59:1585–94.Google Scholar
Holm, IE, Englund, E, Mackenzie, IR, et al. A reassessment of the neuropathology of frontotemporal dementia linked to chromosome 3. J Neuropathol Exp Neurol 2007;66:884–91.Google Scholar
Holm, IE, Isaacs, AM, Mackenzie, IR. Absence of FUS-immunoreactive pathology in frontotemporal dementia linked to chromosome 3 (FTD-3) caused by mutation in the CHMP2B gene. Acta Neuropathol 2009;118:719–20.Google Scholar
Cox, LE, Ferraiuolo, L, Goodall, EF, et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS One 2010;5:e9872.Google Scholar
Skibinski, G, Parkinson, NJ, Brown, JM, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 2005;37:806–8.Google Scholar
Lee, JA, Beigneux, A, Ahmad, ST, et al. ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration. Curr Biol 2007;17:1561–7.Google Scholar
Ghazi-Noori, S, Froud, KE, Mizielinska, S, et al. Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice. Brain 2012;135:819–32.Google Scholar
Thomas, M, Alegre-Abarrategui, J, Wade-Martins, R. RNA dysfunction and aggrephagy at the centre of an amyotrophic lateral sclerosis/frontotemporal dementia disease continuum. Brain 2013;136:1345–60.Google Scholar

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