Dataset Information

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

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.

SUBMITTER: Zhang YJ

PROVIDER: S-EPMC5138863 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Zhang Yong-Jie YJ Gendron Tania F TF Grima Jonathan C JC Sasaguri Hiroki H Jansen-West Karen K Xu Ya-Fei YF Katzman Rebecca B RB Gass Jennifer J Murray Melissa E ME Shinohara Mitsuru M Lin Wen-Lang WL Garrett Aliesha A Stankowski Jeannette N JN Daughrity Lillian L Tong Jimei J Perkerson Emilie A EA Yue Mei M Chew Jeannie J Castanedes-Casey Monica M Kurti Aishe A Wang Zizhao S ZS Liesinger Amanda M AM Baker Jeremy D JD Jiang Jie J Lagier-Tourenne Clotilde C Edbauer Dieter D Cleveland Don W DW Rademakers Rosa R Boylan Kevin B KB Bu Guojun G Link Christopher D CD Dickey Chad A CA Rothstein Jeffrey D JD Dickson Dennis W DW Fryer John D JD Petrucelli Leonard L

Nature neuroscience 20160321 5

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 pro ...[more]

PMID: 26998601

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Project description:Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with available treatments only marginally slowing progression or improving survival. A hexanucleotide repeat expansion mutation in the C9ORF72 gene is the most commonly known genetic cause of both sporadic and familial cases of ALS and frontotemporal dementia (FTD). The C9ORF72 expansion mutation produces five dipeptide repeat proteins (DPRs), and while the mechanistic determinants of DPR-mediated neurotoxicity remain incompletely understood, evidence suggests that disruption of nucleocytoplasmic transport and increased DNA damage contributes to pathology. Therefore, characterizing these disturbances and determining the relative contribution of different DPRs is needed to facilitate the development of novel therapeutics for C9ALS/FTD. To this end, we generated a series of nucleocytoplasmic transport "biosensors", composed of the green fluorescent protein (GFP), fused to different classes of nuclear localization signals (NLSs) and nuclear export signals (NESs). Using these biosensors in conjunction with automated microscopy, we investigated the role of the three most neurotoxic DPRs (PR, GR, and GA) on seven nuclear import and two export pathways. In addition to other DPRs, we found that PR had pronounced inhibitory effects on the classical nuclear export pathway and several nuclear import pathways. To identify compounds capable of counteracting the effects of PR on nucleocytoplasmic transport, we developed a nucleocytoplasmic transport assay and screened several commercially available compound libraries, totaling 2714 compounds. In addition to restoring nucleocytoplasmic transport efficiencies, hits from the screen also counteract the cytotoxic effects of PR. Selected hits were subsequently tested for their ability to rescue another C9ALS/FTD phenotype-persistent DNA double strand breakage. Overall, we found that DPRs disrupt multiple nucleocytoplasmic transport pathways and we identified small molecules that counteract these effects-resulting in increased viability of PR-expressing cells and decreased DNA damage markers in patient-derived motor neurons. Several HDAC inhibitors were validated as hits, supporting previous studies that show that HDAC inhibitors confer therapeutic effects in neurodegenerative models.

Dataset Information

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

Publications

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

Similar Datasets

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