C9ORF72 Poly(GA) Aggregates Sequester and Impair HR23 and Nucleocytoplasmic Transport Proteins

Overview

Journal Nat Neurosci

Date 2016 Mar 22

PMID 26998601

Citations 204

Authors

Yong-Jie Zhang

Tania F Gendron

Jonathan C Grima

Hiroki Sasaguri

Karen Jansen-West

Ya-Fei Xu

Rebecca B Katzman

Jennifer Gass

Melissa E Murray

Mitsuru Shinohara

Wen-Lang Lin

Aliesha Garrett

Jeannette N Stankowski

Lillian Daughrity

Jimei Tong

Emilie A Perkerson

Mei Yue

Jeannie Chew

Monica Castanedes-Casey

Aishe Kurti

Zizhao S Wang

Amanda M Liesinger

Jeremy D Baker

Jie Jiang

Clotilde Lagier-Tourenne

Dieter Edbauer

Don W Cleveland

Rosa Rademakers

Kevin B Boylan

Guojun Bu

Christopher D Link

Chad A Dickey

Jeffrey D Rothstein

Dennis W Dickson

John D Fryer

Leonard Petrucelli

Affiliations

Soon will be listed here.

Abstract

Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.

Citing Articles

Neuronal polyunsaturated fatty acids are protective in ALS/FTD.

Giblin A, Cammack A, Blomberg N, Anoar S, Mikheenko A, Carcole M Nat Neurosci. 2025; .

PMID: 40000803 DOI: 10.1038/s41593-025-01889-3.

A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (GC) mouse model.

Thompson E, Spead O, Akerman S, Curcio C, Zaepfel B, Kent E Acta Neuropathol Commun. 2024; 12(1):203.

PMID: 39722074 PMC: 11670477. DOI: 10.1186/s40478-024-01911-y.

A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV- C9ORF72 (G 4 C 2) 66 mouse model.

Thompson E, Spead O, Akerman S, Curcio C, Zaepfel B, Kent E Res Sq. 2024; .

PMID: 39711523 PMC: 11661372. DOI: 10.21203/rs.3.rs-5221595/v1.

Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases.

Jiang L, Zhang X, Hu H Int J Mol Sci. 2024; 25(22).

PMID: 39596445 PMC: 11594478. DOI: 10.3390/ijms252212380.

Proteostasis and Its Role in Disease Development.

Shukla M, Narayan M Cell Biochem Biophys. 2024; .

PMID: 39422790 DOI: 10.1007/s12013-024-01581-6.

References

Woerner A, Frottin F, Hornburg D, Feng L, Meissner F, Patra M . Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science. 2015; 351(6269):173-6. DOI: 10.1126/science.aad2033. View

Zhang Y, Rohde L, Wu H . Involvement of nucleotide excision and mismatch repair mechanisms in double strand break repair. Curr Genomics. 2009; 10(4):250-8. PMC: 2709936. DOI: 10.2174/138920209788488544. View

Shinohara M, Petersen R, Dickson D, 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. 2013; 125(4):535-47. PMC: 3612369. DOI: 10.1007/s00401-013-1086-9. View

May S, Hornburg D, Schludi M, Arzberger T, Rentzsch K, Schwenk B . C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol. 2014; 128(4):485-503. PMC: 4159571. DOI: 10.1007/s00401-014-1329-4. View

Dantuma N, Heinen C, Hoogstraten D . The ubiquitin receptor Rad23: at the crossroads of nucleotide excision repair and proteasomal degradation. DNA Repair (Amst). 2009; 8(4):449-60. DOI: 10.1016/j.dnarep.2009.01.005. View

Le Ber I, Camuzat A, Guerreiro R, Bouya-Ahmed K, Bras J, Nicolas G . SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis. JAMA Neurol. 2013; 70(11):1403-10. PMC: 4199096. DOI: 10.1001/jamaneurol.2013.3849. View

Chakrabarty P, Rosario A, Cruz P, Siemienski Z, Ceballos-Diaz C, Crosby K . Capsid serotype and timing of injection determines AAV transduction in the neonatal mice brain. PLoS One. 2013; 8(6):e67680. PMC: 3692458. DOI: 10.1371/journal.pone.0067680. View

Gendron T, Bieniek K, Zhang Y, Jansen-West K, Ash P, Caulfield T . 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(6):829-44. PMC: 3830741. DOI: 10.1007/s00401-013-1192-8. View

Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T . Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science. 2014; 345(6201):1139-45. PMC: 4459787. DOI: 10.1126/science.1254917. View

10.

Lee Y, Chen H, Peres J, Gomez-Deza J, Attig J, Stalekar M . Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 2013; 5(5):1178-86. PMC: 3898469. DOI: 10.1016/j.celrep.2013.10.049. View

11.

Donnelly C, Zhang P, Pham J, Haeusler A, Heusler A, Mistry N . RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron. 2013; 80(2):415-28. PMC: 4098943. DOI: 10.1016/j.neuron.2013.10.015. View

12.

Schludi M, May S, Grasser F, Rentzsch K, Kremmer E, Kupper C . Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol. 2015; 130(4):537-55. PMC: 4575390. DOI: 10.1007/s00401-015-1450-z. View

13.

Ng J, Vrieling H, Sugasawa K, Ooms M, Grootegoed J, Vreeburg J . Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B. Mol Cell Biol. 2002; 22(4):1233-45. PMC: 134644. DOI: 10.1128/MCB.22.4.1233-1245.2002. View

14.

Mori K, Weng S, Arzberger T, May S, Rentzsch K, Kremmer E . The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013; 339(6125):1335-8. DOI: 10.1126/science.1232927. View

15.

Deng H, Chen W, Hong S, Boycott K, Gorrie G, Siddique N . Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011; 477(7363):211-5. PMC: 3169705. DOI: 10.1038/nature10353. View

16.

Mocanu M, Nissen A, Eckermann K, Khlistunova I, Biernat J, Drexler D . 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. 2008; 28(3):737-48. PMC: 6670355. DOI: 10.1523/JNEUROSCI.2824-07.2008. View

17.

Xi Z, Zinman L, Moreno D, Schymick J, Liang Y, Sato C . Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. Am J Hum Genet. 2013; 92(6):981-9. PMC: 3675239. DOI: 10.1016/j.ajhg.2013.04.017. View

18.

Chiba T, Hagihara Y, Higurashi T, Hasegawa K, Naiki H, Goto Y . 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. 2003; 278(47):47016-24. DOI: 10.1074/jbc.M304473200. View

19.

Todd T, Lim J . Aggregation formation in the polyglutamine diseases: protection at a cost?. Mol Cells. 2013; 36(3):185-94. PMC: 3800151. DOI: 10.1007/s10059-013-0167-x. View

20.

DeJesus-Hernandez M, Mackenzie I, Boeve B, Boxer A, Baker M, Rutherford N . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011; 72(2):245-56. PMC: 3202986. DOI: 10.1016/j.neuron.2011.09.011. View