C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins

Nature Neuroscience

Volumn 19, Issue 5, 2016, Pages 668-677

  Zhang, Yong Jie ^a   Gendron, Tania F ^a   Grima, Jonathan C ^b   Sasaguri, Hiroki ^a   Jansen West, Karen ^a   Xu, Ya Fei ^a   Katzman, Rebecca B ^a   Gass, Jennifer ^a   Murray, Melissa E ^a   Shinohara, Mitsuru ^a   Lin, Wen Lang ^a   Garrett, Aliesha ^a   Stankowski, Jeannette N ^a   Daughrity, Lillian ^a   Tong, Jimei ^a   Perkerson, Emilie A ^a   Yue, Mei ^a   Chew, Jeannie ^a,c   Castanedes Casey, Monica ^a   Kurti, Aishe ^a   Wang, Zizhao S ^a   Liesinger, Amanda M ^a   Baker, Jeremy D ^d   Jiang, Jie ^e   Lagier Tourenne, Clotilde ^f   Edbauer, Dieter ^g,h,i   Cleveland, Don W ^e   Rademakers, Rosa ^a   Boylan, Kevin B ^j   Bu, Guojun ^a   Link, Christopher D ^k   Dickey, Chad A ^d   Rothstein, Jeffrey D ^b   Dickson, Dennis W ^a   Fryer, John D ^a,c   Petrucelli, Leonard ^a   more..

^a MAYO GRADUATE SCHOOL   (United States)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c MAYO CLINIC   (United States)

^d UNIVERSITY OF SOUTH FLORIDA   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

^f MASSACHUSETTS GENERAL HOSPITAL   (United States)

^g GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^h UNIVERSITY OF MUNICH   (Germany)

ⁱ Munich Cluster of Systems Neurology ^*  (Germany)

^j MAYO CLINIC   (United States)

^k UNIVERSITY OF COLORADO   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

HR23 PROTEIN; NUCLEOCYTOPLASMIC TRANSPORT PROTEIN; POLY(GA) PROTEIN; UBIQUITINATED PROTEIN; UNCLASSIFIED DRUG; XERODERMA PIGMENTOSUM GROUP C PROTEIN; C9ORF72 PROTEIN, MOUSE; CARRIER PROTEIN; DNA BINDING PROTEIN; GUANINE NUCLEOTIDE EXCHANGE FACTOR; POLY(GLYCYL-ALANYL); PROTEIN; RAD23A PROTEIN, MOUSE; RAD23B PROTEIN, MOUSE; TDP-43 PROTEIN, MOUSE; XPC PROTEIN, MOUSE;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; C9ORF72 GENE; FRONTOTEMPORAL DEMENTIA; GENE; MOUSE; NERVE DEGENERATION; NEUROPATHOLOGY; NEUROTOXICITY; NONHUMAN; NUCLEOCYTOPLASMIC TRANSPORT; PHENOTYPE; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN DEFECT; TDP 43 PROTEINOPATHY; ANIMAL; ANIMAL BEHAVIOR; ATROPHY; BRAIN; CELL INCLUSION; GENE EXPRESSION; GENETICS; HUMAN; METABOLISM; MUTATION; NERVE CELL; PATHOLOGY; PRIMARY CELL CULTURE; ULTRASTRUCTURE;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMALS; ATROPHY; BEHAVIOR, ANIMAL; BRAIN; CARRIER PROTEINS; DNA-BINDING PROTEINS; FRONTOTEMPORAL DEMENTIA; GENE EXPRESSION; GUANINE NUCLEOTIDE EXCHANGE FACTORS; HUMANS; INCLUSION BODIES; MICE; MUTATION; NERVE DEGENERATION; NEURONS; PRIMARY CELL CULTURE; PROTEINS; UBIQUITINATED PROTEINS;

EID: 84961391578     PISSN: 10976256     EISSN: 15461726     Source Type: Journal    
DOI: 10.1038/nn.4272     Document Type: Article

References (57)

1. 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).
2. 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).
3. Belzil, V.V. et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol. 126, 895-905 (2013).
4. Liu, E.Y. et al. C9orf72 hypermethylation protects against repeat expansion-Associated pathology in ALS/FTD. Acta Neuropathol. 128, 525-541 (2014).
5. Xi, Z. et al. Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am. J. Hum. Genet. 92, 981-989 (2013).
6. van Blitterswijk, M. et al. Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72. Acta Neuropathol. 130, 863-876 (2015).
7. Gendron, T.F., Belzil, V.V., Zhang, Y.J. & Petrucelli, L. Mechanisms of toxicity in C9FTLD/ALS. Acta Neuropathol. 127, 359-376 (2014).
8. Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci. Transl. Med. 5, 208ra149 (2013).
9. Donnelly, C.J. et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80, 415-428 (2013).
10. Cooper-Knock, J. et al. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137, 2040-2051 (2014).
11. Lee, Y.B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178-1186 (2013).
12. Freibaum, B.D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129-133 (2015).
13. Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56-61 (2015).
14. Gendron, T.F. 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. 126, 829-844 (2013).
15. Ash, P.E. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639-646 (2013).
16. Mori, K. et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol. 126, 881-893 (2013).
17. Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335-1338 (2013).
18. Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl. Acad. Sci. USA 110, E4968-E4977 (2013).
19. Jovičić, A. et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat. Neurosci. 18, 1226-1229 (2015).
20. Yamakawa, M. et al. Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum. Mol. Genet. 24, 1630-1645 (2014).
21. Mizielinska, S. et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345, 1192-1194 (2014).
22. May, S. et al. C9orf72 FTLD/ALS-Associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 128, 485-503 (2014).
23. Wen, X. 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 84, 1213-1225 (2014).
24. Kwon, I. et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345, 1139-1145 (2014).
25. Zhang, Y.J. et al. Aggregation-prone c9FTD/ALS poly(GA) RAN-Translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 128, 505-524 (2014).
26. Tao, Z. et al. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum. Mol. Genet. 24, 2426-2441 (2015).
27. Mackenzie, I.R. et al. Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol. 130, 845-861 (2015).
28. Schludi, M.H. et al. Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol. 130, 537-555 (2015).
29. Woerner, A.C. et al. Cytoplasmic protein aggregates interfere with nucleo-cytoplasmic transport of protein and RNA. Science 351, 173-176 (2015).
30. Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440-1446 (2011).
31. Le Ber, I. et al. French Clinical and Genetic Research Network on FTD/FTD-ALS. SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis. JAMA Neurol. 70, 1403-1410 (2013).
32. 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).
33. Dougan, L., Li, J., Badilla, C.L., Berne, B.J. & Fernandez, J.M. Single homopolypeptide chains collapse into mechanically rigid conformations. Proc. Natl. Acad. Sci. USA 106, 12605-12610 (2009).
34. Popiel, H.A. et al. Disruption of the toxic conformation of the expanded polyglutamine stretch leads to suppression of aggregate formation and cytotoxicity. Biochem. Biophys. Res. Commun. 317, 1200-1206 (2004).
35. Pelassa, I. et al. Association of polyalanine and polyglutamine coiled coils mediates expansion disease-related protein aggregation and dysfunction. Hum. Mol. Genet. 23, 3402-3420 (2014).
36. Chiba, T. et al. Amyloid fibril formation in the context of full-length protein: effects of proline mutations on the amyloid fibril formation of beta2-microglobulin. J. Biol. Chem. 278, 47016-47024 (2003).
37. Mocanu, M.M. et al. The potential for beta-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. 28, 737-748 (2008).
38. Dantuma, N.P., Heinen, C. & Hoogstraten, D. The ubiquitin receptor Rad23: At the crossroads of nucleotide excision repair and proteasomal degradation. DNA Repair (Amst.) 8, 449-460 (2009).
39. Chew, J. et al. Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348, 1151-1154 (2015).
40. Mitchell, J.M., Mansfeld, J., Capitanio, J., Kutay, U. & Wozniak, R.W. Pom121 links two essential subcomplexes of the nuclear pore complex core to the membrane. J. Cell Biol. 191, 505-521 (2010).
41. Antonin, W., Franz, C., Haselmann, U., Antony, C. & Mattaj, I.W. The integral membrane nucleoporin pom121 functionally links nuclear pore complex assembly and nuclear envelope formation. Mol. Cell 17, 83-92 (2005).
42. Ng, J.M. et al. A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Genes Dev. 17, 1630-1645 (2003).
43. Melis, J.P.M., Luijten, M., Mullenders, L.H.F. & van Steeg, H. The role of XPC: implications in cancer and oxidative DNA damage. Mutat. Res. 728, 107-117 (2011).
44. Zhang, Y., Rohde, L.H. & Wu, H. Involvement of nucleotide excision and mismatch repair mechanisms in double strand break repair. Curr. Genomics 10, 250-258 (2009).
45. Ng, J.M. et al. Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B. Mol. Cell. Biol. 22, 1233-1245 (2002).
46. Davidson, Y. et al. Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins. Neuropathol. Appl. Neurobiol. Published online 5 November 2015 (doi:10.1111/nan.12292).
47. Todd, T.W. & Lim, J. Aggregation formation in the polyglutamine diseases: protection at a cost? Mol. Cells 36, 185-194 (2013).
48. Bergink, S. et al. The DNA repair-ubiquitin-Associated HR23 proteins are constituents of neuronal inclusions in specific neurodegenerative disorders without hampering DNA repair. Neurobiol. Dis. 23, 708-716 (2006).
49. Chakrabarty, P. et al. Capsid serotype and timing of injection determines AAV transduction in the neonatal mice brain. PLoS One 8, e67680 (2013).
50. Kim, J.Y. et al. Viral transduction of the neonatal brain delivers controllable genetic mosaicism for visualising and manipulating neuronal circuits in vivo. Eur. J. Neurosci. 37, 1203-1220 (2013).
51. Xu, Y.F. et al. Wild-Type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J. Neurosci. 30, 10851-10859 (2010).
52. Lin, W.L., Dickson, D.W. & Sahara, N. Immunoelectron microscopic and biochemical studies of caspase-cleaved tau in a mouse model of tauopathy. J. Neuropathol. Exp. Neurol. 70, 779-787 (2011).
53. Murray, M.E. et al. A quantitative postmortem MRI design sensitive to white matter hyperintensity differences and their relationship with underlying pathology. J. Neuropathol. Exp. Neurol. 71, 1113-1122 (2012).
54. Shinohara, M., Petersen, R.C., Dickson, D.W. & Bu, G. Brain regional correlation of amyloid-β with synapses and apolipoprotein E in non-demented individuals: potential mechanisms underlying regional vulnerability to amyloid-β accumulation. Acta Neuropathol. 125, 535-547 (2013).
55. Zhang, Y.J. et al. Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc. Natl. Acad. Sci. USA 106, 7607-7612 (2009).
56. Gendron, T.F. et al. Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Acta Neuropathol. 130, 559-573 (2015).
57. Cook, C. et al. Severe amygdala dysfunction in a MAPT transgenic mouse model of frontotemporal dementia. Neurobiol. Aging 35, 1769-1777 (2014).