An amyloid-like cascade hypothesis for C9orf72 ALS/FTD

Current Opinion in Neurobiology

Volumn 36, Issue , 2016, Pages 99-106

  Edbauer, Dieter ^a,b,c   Haass, Christian ^a,b,c  

^a GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^b Germany 3 Munich Cluster for Systems Neurology   (Germany)

^c UNIVERSITY OF MUNICH   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID; DIPEPTIDE REPEAT PROTEIN; PEPTIDES AND PROTEINS; TAR DNA BINDING PROTEIN; UNCLASSIFIED DRUG; C9ORF72 PROTEIN, HUMAN; DIPEPTIDE; PROTEIN; REPETITIVE DNA; RNA BINDING PROTEIN;

AMYOTROPHIC LATERAL SCLEROSIS; BRAIN ATROPHY; C9ORF72 GENE; COGNITIVE DEFECT; CROSS-SECTIONAL STUDY; FRONTOTEMPORAL DEMENTIA; GAIN OF FUNCTION MUTATION; GENE; HUMAN; LOSS OF FUNCTION MUTATION; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; ATROPHY; BRAIN; GENETICS; METABOLISM; PATHOLOGY; PROTEINOSIS; TDP 43 PROTEINOPATHY;

AMYOTROPHIC LATERAL SCLEROSIS; ATROPHY; BRAIN; COGNITION DISORDERS; DIPEPTIDES; DNA REPEAT EXPANSION; FRONTOTEMPORAL DEMENTIA; HUMANS; PROTEIN AGGREGATION, PATHOLOGICAL; PROTEINS; RNA-BINDING PROTEINS; TDP-43 PROTEINOPATHIES;

EID: 84946606180     PISSN: 09594388     EISSN: 18736882     Source Type: Journal    
DOI: 10.1016/j.conb.2015.10.009     Document Type: Review

References (63)

1. Dormann D., Haass C. TDP-43 FUS: a nuclear affair. Trends Neurosci 2011, 34:339-348.
2. Rademakers R., Neumann M., Mackenzie I.R. Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 2012, 8:423-434.
3. Neumann M., Sampathu D.M., Kwong L.K., Truax A.C., Micsenyi M.C., Chou T.T., Bruce J., Schuck T., Grossman M., Clark C.M., et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006, 314:130-133.
4. Kabashi E., Valdmanis P.N., Dion P., Spiegelman D., McConkey B.J., Vande Velde C., Bouchard J.P., Lacomblez L., Pochigaeva K., Salachas F., et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 2008, 40:572-574.
5. Scotter E.L., Chen H.J., Shaw C.E. TDP-43 proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics 2015, 12:352-363.
6. Irwin D.J., Cairns N.J., Grossman M., McMillan C.T., Lee E.B., Van Deerlin V.M., Lee V.M., Trojanowski J.Q. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol 2015, 129:469-491.
7. DeJesus-Hernandez M., Mackenzie I.R., Boeve B.F., Boxer A.L., Baker M., Rutherford N.J., Nicholson A.M., Finch N.A., Flynn H., Adamson J., et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011, 72:245-256.
8. Renton A.E., Majounie E., Waite A., Simon-Sanchez J., Rollinson S., Gibbs J.R., Schymick J.C., Laaksovirta H., van Swieten J.C., Myllykangas L., et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011, 72:257-268.
9. Gijselinck I., Van Langenhove T., van der Zee J., Sleegers K., Philtjens S., Kleinberger G., Janssens J., Bettens K., Van Cauwenberghe C., Pereson S., 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, 11:54-65.
10. van der Zee J., Gijselinck I., Dillen L., Van Langenhove T., Theuns J., Engelborghs S., Philtjens S., Vandenbulcke M., Sleegers K., Sieben A., et al. A Pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability and intermediate repeats. Hum Mutat 2013, 34:363-373.
11. Majounie E., Renton A.E., Mok K., Dopper E.G., Waite A., Rollinson S., Chio A., Restagno G., Nicolaou N., Simon-Sanchez J., 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, 11:323-330.
12. Waite A.J., Baumer D., East S., Neal J., Morris H.R., Ansorge O., Blake D.J. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol Aging 2014, 35. 1779 e1775-1779 e1713.
13. Koppers M., Blokhuis A.M., Westeneng H.J., Terpstra M.L., Zundel C.A., Vieira de Sa R., Schellevis R.D., Waite A.J., Blake D.J., Veldink J.H., et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 2015, 78:426-438.
14. Mori K., Lammich S., Mackenzie I.R., Forne I., Zilow S., Kretzschmar H., Edbauer D., Janssens J., Kleinberger G., Cruts M., 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, 125:413-423.
15. Cooper-Knock J., Walsh M.J., Higginbottom A., Robin Highley J., Dickman M.J., Edbauer D., Ince P.G., Wharton S.B., Wilson S.A., Kirby J., et al. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 2014, 137:2040-2051.
16. Donnelly C.J., Zhang P.W., Pham J.T., Haeusler A.R., Mistry N.A., Vidensky S., Daley E.L., Poth E.M., Hoover B., Fines D.M., et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 2013, 80:415-428.
17. Haeusler A.R., Donnelly C.J., Periz G., Simko E.A., Shaw P.G., Kim M.S., Maragakis N.J., Troncoso J.C., Pandey A., Sattler R., et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 2014, 507:195-200.
18. Al-Sarraj S., King A., Troakes C., Smith B., Maekawa S., Bodi I., Rogelj B., Al-Chalabi A., Hortobagyi T. Shaw CE: 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 2011, 122:691-702.
19. Mori K., Weng S.M., Arzberger T., May S., Rentzsch K., Kremmer E., Schmid B., Kretzschmar H.A., Cruts M., Van Broeckhoven C., et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013, 15:1335-1338.
20. Ash P.E., Bieniek K.F., Gendron T.F., Caulfield T., Lin W.L., Dejesus-Hernandez M., van Blitterswijk M.M., Jansen-West K., Paul J.W., Rademakers R., et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 2013, 77:639-646.
21. Zu T., Liu Y., Banez-Coronel M., Reid T., Pletnikova O., Lewis J., Miller T.M., Harms M.B., Falchook A.E., Subramony S.H., et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A 2013, 110:E4968-E4977.
22. Gendron T.F., Bieniek K.F., Zhang Y.J., Jansen-West K., Ash P.E., Caulfield T., Daughrity L., Dunmore J.H., Castanedes-Casey M., Chew J., 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, 126:829-844.
23. Mori K., Arzberger T., Grasser F.A., Gijselinck I., May S., Rentzsch K., Weng S.M., Schludi M.H., van der Zee J., Cruts M., et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 2013, 126:881-893.
24. Zu T., Gibbens B., Doty N.S., Gomes-Pereira M., Huguet A., Stone M.D., Margolis J., Peterson M., Markowski T.W., Ingram M.A., et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 2011, 108:260-265.
25. Todd P.K., Oh S.Y., Krans A., He F., Sellier C., Frazer M., Renoux A.J., Chen K.C., Scaglione K.M., Basrur V., et al. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 2013, 78:440-455.
26. Su Z., Zhang Y., Gendron T.F., Bauer P.O., Chew J., Yang W.Y., Fostvedt E., Jansen-West K., Belzil V.V., Desaro P., et al. Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 2014, 83:1043-1050.
27. Russ J., Liu E.Y., Wu K., Neal D., Suh E., Irwin D.J., McMillan C.T., Harms M.B., Cairns N.J., Wood E.M., et al. Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 2015, 129:39-52.
28. Lagier-Tourenne C., Baughn M., Rigo F., Sun S., Liu P., Li H.R., Jiang J., Watt A.T., Chun S., Katz M., et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc Natl Acad Sci U S A 2013, 110:E4530-E4539.
29. Hornburg D., Drepper C., Butter F., Meissner F., Sendtner M., Mann M. Deep proteomic evaluation of primary and cell line motoneuron disease models delineates major differences in neuronal characteristics. Mol Cell Proteomics 2014, 13:3410-3420.
30. Levine T.P., Daniels R.D., Gatta A.T., Wong L.H., Hayes M.J. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 2013, 29:499-503.
31. Farg M.A., Sundaramoorthy V., Sultana J.M., Yang S., Atkinson R.A., Levina V., Halloran M.A., Gleeson P.A., Blair I.P., Soo K.Y., et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet 2014, 23:3579-3595.
32. Xiao S., MacNair L., McGoldrick P., McKeever P.M., McLean J.R., Zhang M., Keith J., Zinman L., Rogaeva E., Robertson J. Isoform specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol 2015, 78:568-583.
33. Almeida S., Gascon E., Tran H., Chou H.J., Gendron T.F., Degroot S., Tapper A.R., Sellier C., Charlet-Berguerand N., Karydas A., et al. Modeling key pathological features of frontotemporal dementia with C9ORF72 repeat expansion in iPSC-derived human neurons. Acta Neuropathol 2013, 126:385-399.
34. Devlin A.C., Burr K., Borooah S., Foster J.D., Cleary E.M., Geti I., Vallier L., Shaw C.E., Chandran S., Miles G.B. Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat Commun 2015, 6:5999.
35. Sareen D., O'Rourke J.G., Meera P., Muhammad A.K., Grant S., Simpkinson M., Bell S., Carmona S., Ornelas L., Sahabian A., et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 2013, 5:208ra149.
36. May S., Hornburg D., Schludi M.H., Arzberger T., Rentzsch K., Schwenk B.M., Grasser F.A., Mori K., Kremmer E., Banzhaf-Strathmann J., et al. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol 2014, 128:485-503.
37. Zhang Y.J., Jansen-West K., Xu Y.F., Gendron T.F., Bieniek K.F., Lin W.L., Sasaguri H., Caulfield T., Hubbard J., Daughrity L., et al. Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 2014, 128:505-524.
38. Yamakawa M., Ito D., Honda T., Kubo K.I., Noda M., Nakajima K., Suzuki N. Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum Mol Genet 2014, 24:1630-1645.
39. Wen X., Tan W., Westergard T., Krishnamurthy K., Markandaiah S.S., Shi Y., Lin S., Shneider N.A., Monaghan J., Pandey U.B., et al. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 2014, 84:1213-1225.
40. Tao Z., Wang H., Xia Q., Li K., Jiang X., Xu G., Wang G., Ying Z. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet 2015, 24:2426-2441.
41. Kwon I., Xiang S., Kato M., Wu L., Theodoropoulos P., Wang T., Kim J., Yun J., Xie Y., McKnight S.L. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 2014, 345:1139-1145.
42. Schludi M.H., May S., Grasser F.A., Rentzsch K., Kremmer E., Küpper C., Klopstock T., German Consortium for Frontotemporal Lobar Degeneration, Bavarian Brain Banking Alliance, Arzberger T., et al. Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol 2015, 130:537-555.
43. Yang D., Abdallah A., Li Z., Lu Y., Almeida S., Gao F.B. FTD/ALS-associated poly(GR) protein impairs the Notch pathway and is recruited by poly(GA) into cytoplasmic inclusions. Acta Neuropathol 2015, 130:525-535.
44. Mizielinska S., Gronke S., Niccoli T., Ridler C.E., Clayton E.L., Devoy A., Moens T., Norona F.E., Woollacott I.O., Pietrzyk J., et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 2014, 345:1192-1194.
45. Tran H., Almeida S., Moore J., Gendron T.F., Chalasani U., Lu Y., Du X., Nickerson J.A., Petrucelli L., Weng Z., et al. Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a drosophila model of C9ORF72 FTD/ALS. Neuron 2015, 87:1207-1214.
46. Zhang K., Donnelly C.J., Haeusler A.R., Grima J.C., Machamer J.B., Steinwald P., Daley E.L., Miller S.J., Cunningham K.M., Vidensky S., et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 2015, 525:56-61.
47. Freibaum B.D., Lu Y., Lopez-Gonzalez R., Kim N.C., Almeida S., Lee K.H., Badders N., Valentine M., Miller B.L., Wong P.C., et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 2015, 525:129-133.
48. Jovicic A., Mertens J., Boeynaems S., Bogaert E., Chai N., Yamada S.B., Paul J.W., Sun S., Herdy J.R., Bieri G., et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 2015, 18:1226-1229.
49. Zhang J., Ito H., Wate R., Ohnishi S., Nakano S., Kusaka H. Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis. Acta Neuropathol 2006, 112:673-680.
50. Dormann D., Rodde R., Edbauer D., Bentmann E., Fischer I., Hruscha A., Than M.E., Mackenzie I.R., Capell A., Schmid B., et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 2010, 29:2841-2857.
51. Chew J., Gendron T.F., Prudencio M., Sasaguri H., Zhang Y.J., Castanedes-Casey M., Lee C.W., Jansen-West K., Kurti A., Murray M.E., et al. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 2015, 348:1151-1154.
52. Cooper-Knock J., Higginbottom A., Stopford M.J., Highley J.R., Ince P.G., Wharton S.B., Pickering-Brown S., Kirby J., Hautbergue G.M., Shaw P.J. Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol 2015, 130:63-75.
53. Mackenzie I.R., Arzberger T., Kremmer E., Troost D., Lorenzl S., Mori K., Weng S.M., Haass C., Kretzschmar H.A., Edbauer D., et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol 2013, 126:859-879.
54. Davidson Y.S., Barker H., Robinson A.C., Thompson J.C., Harris J., Troakes C., Smith B., Al-Saraj S., Shaw C., Rollinson S., et al. Brain distribution of dipeptide repeat proteins in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9ORF72. Acta Neuropathol Commun 2014, 2:70.
55. Gomez-Deza J., Lee Y.B., Troakes C., Nolan M., Al-Sarraj S., Gallo J.M., Shaw C.E. Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. Acta Neuropathol Commun 2015, 3:38.
56. Musiek E.S., Holtzman D.M. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat Neurosci 2015, 18:800-806.
57. Proudfoot M., Gutowski N.J., Edbauer D., Hilton D.A., Stephens M., Rankin J., Mackenzie I.R. Early dipeptide repeat pathology in a frontotemporal dementia kindred with C9ORF72 mutation and intellectual disability. Acta Neuropathol 2014, 127:451-458.
58. Mann D.M. Dipeptide repeat protein toxicity in frontotemporal lobar degeneration and in motor neurone disease associated with expansions in C9ORF72 - a cautionary note. Neurobiol Aging 2015, 36:1224-1226.
59. Van Deerlin V.M., Leverenz J.B., Bekris L.M., Bird T.D., Yuan W., Elman L.B., Clay D., Wood E.M., Chen-Plotkin A.S., Martinez-Lage M., et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 2008, 7:409-416.
60. Bateman R.J., Xiong C., Benzinger T.L., Fagan A.M., Goate A., Fox N.C., Marcus D.S., Cairns N.J., Xie X., Blazey T.M., et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 2012, 367:795-804.
61. Rohrer J.D., Nicholas J.M., Cash D.M., van Swieten J., Dopper E., Jiskoot L., van Minkelen R., Rombouts S.A., Cardoso M.J., Clegg S., et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol 2015, 14:253-262.
62. Hardy J.A., Higgins G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science 1992, 256:184-185.
63. Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002, 297:353-356.