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

Yongjie Zhang, Tania D 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 KurtiZizhao S. Wang, Amanda M. Liesinger, Jeremy D. Baker, Jie Jiang, Clotilde Lagier-Tourenne, Dieter Edbauer, Don W. Cleveland, Rosa V Rademakers, Kevin B. Boylan, Guojun D Bu, Christopher D. Link, Chad A. Dickey, Jeffrey D. Rothstein, Dennis W Dickson, John D. Fryer, Leonard Petrucelli

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Neuronal inclusions of poly(GA), a protein unconventionally translated from G 4 C 2 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.

Original languageEnglish (US)
Pages (from-to)668-677
Number of pages10
JournalNature Neuroscience
Volume19
Issue number5
DOIs
StatePublished - May 1 2016

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Nucleocytoplasmic Transport Proteins
Cell Nucleus Active Transport
Pathology
Ubiquitinated Proteins
Xeroderma Pigmentosum
Proteolysis
Proteins
Phenotype
Mutation
Frontotemporal Dementia With Motor Neuron Disease

ASJC Scopus subject areas

  • Neuroscience(all)

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C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. / Zhang, Yongjie; Gendron, Tania D; Grima, Jonathan C.; Sasaguri, Hiroki; Jansen-West, Karen; Xu, Ya Fei; Katzman, Rebecca B.; Gass, Jennifer; Murray, Melissa E; Shinohara, Mitsuru; Lin, Wen Lang; Garrett, Aliesha; Stankowski, Jeannette N.; Daughrity, Lillian; Tong, Jimei; Perkerson, Emilie A.; Yue, Mei; Chew, Jeannie; Castanedes-Casey, Monica; Kurti, Aishe; Wang, Zizhao S.; Liesinger, Amanda M.; Baker, Jeremy D.; Jiang, Jie; Lagier-Tourenne, Clotilde; Edbauer, Dieter; Cleveland, Don W.; Rademakers, Rosa V; Boylan, Kevin B.; Bu, Guojun D; Link, Christopher D.; Dickey, Chad A.; Rothstein, Jeffrey D.; Dickson, Dennis W; Fryer, John D.; Petrucelli, Leonard.

In: Nature Neuroscience, Vol. 19, No. 5, 01.05.2016, p. 668-677.

Research output: Contribution to journalArticle

Zhang, Y, Gendron, TD, Grima, JC, Sasaguri, H, Jansen-West, K, Xu, YF, Katzman, RB, Gass, J, Murray, ME, Shinohara, M, Lin, WL, Garrett, A, Stankowski, JN, Daughrity, L, Tong, J, Perkerson, EA, Yue, M, Chew, J, Castanedes-Casey, M, Kurti, A, Wang, ZS, Liesinger, AM, Baker, JD, Jiang, J, Lagier-Tourenne, C, Edbauer, D, Cleveland, DW, Rademakers, RV, Boylan, KB, Bu, GD, Link, CD, Dickey, CA, Rothstein, JD, Dickson, DW, Fryer, JD & Petrucelli, L 2016, 'C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins', Nature Neuroscience, vol. 19, no. 5, pp. 668-677. https://doi.org/10.1038/nn.4272
Zhang, Yongjie ; Gendron, Tania D ; Grima, Jonathan C. ; Sasaguri, Hiroki ; Jansen-West, Karen ; Xu, Ya Fei ; Katzman, Rebecca B. ; Gass, Jennifer ; Murray, Melissa E ; Shinohara, Mitsuru ; Lin, Wen Lang ; Garrett, Aliesha ; Stankowski, Jeannette N. ; Daughrity, Lillian ; Tong, Jimei ; Perkerson, Emilie A. ; Yue, Mei ; Chew, Jeannie ; Castanedes-Casey, Monica ; Kurti, Aishe ; Wang, Zizhao S. ; Liesinger, Amanda M. ; Baker, Jeremy D. ; Jiang, Jie ; Lagier-Tourenne, Clotilde ; Edbauer, Dieter ; Cleveland, Don W. ; Rademakers, Rosa V ; Boylan, Kevin B. ; Bu, Guojun D ; Link, Christopher D. ; Dickey, Chad A. ; Rothstein, Jeffrey D. ; Dickson, Dennis W ; Fryer, John D. ; Petrucelli, Leonard. / C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. In: Nature Neuroscience. 2016 ; Vol. 19, No. 5. pp. 668-677.
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abstract = "Neuronal inclusions of poly(GA), a protein unconventionally translated from G 4 C 2 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.",
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T1 - C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins

AU - Zhang, Yongjie

AU - Gendron, Tania D

AU - Grima, Jonathan C.

AU - Sasaguri, Hiroki

AU - Jansen-West, Karen

AU - Xu, Ya Fei

AU - Katzman, Rebecca B.

AU - Gass, Jennifer

AU - Murray, Melissa E

AU - Shinohara, Mitsuru

AU - Lin, Wen Lang

AU - Garrett, Aliesha

AU - Stankowski, Jeannette N.

AU - Daughrity, Lillian

AU - Tong, Jimei

AU - Perkerson, Emilie A.

AU - Yue, Mei

AU - Chew, Jeannie

AU - Castanedes-Casey, Monica

AU - Kurti, Aishe

AU - Wang, Zizhao S.

AU - Liesinger, Amanda M.

AU - Baker, Jeremy D.

AU - Jiang, Jie

AU - Lagier-Tourenne, Clotilde

AU - Edbauer, Dieter

AU - Cleveland, Don W.

AU - Rademakers, Rosa V

AU - Boylan, Kevin B.

AU - Bu, Guojun D

AU - Link, Christopher D.

AU - Dickey, Chad A.

AU - Rothstein, Jeffrey D.

AU - Dickson, Dennis W

AU - Fryer, John D.

AU - Petrucelli, Leonard

PY - 2016/5/1

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N2 - Neuronal inclusions of poly(GA), a protein unconventionally translated from G 4 C 2 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.

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