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

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 KurtiZizhao 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

Research output: Contribution to journalArticlepeer-review

155 Scopus citations


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
Issue number5
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Neuroscience(all)


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