Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology

Author:

Anderson Eric N1,Morera Andrés A2,Kour Sukhleen1,Cherry Jonathan D34,Ramesh Nandini1,Gleixner Amanda56,Schwartz Jacob C2,Ebmeier Christopher7ORCID,Old William7,Donnelly Christopher J56ORCID,Cheng Jeffrey P8,Kline Anthony E89,Kofler Julia10,Stein Thor D34,Pandey Udai Bhan111ORCID

Affiliation:

1. Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center

2. Department of Chemistry and Biochemistry, University of Arizona

3. Department of Pathology and Laboratory Medicine, Boston University School of Medicine

4. Boston VA Healthcare System

5. Department of Neurobiology, University of Pittsburgh School of Medicine

6. LiveLike Lou Center for ALS Research, Brain Institute, University of Pittsburgh School of Medicine

7. Molecular, Cellular & Developmental Biology, University of Colorado

8. Physical Medicine & Rehabilitation; Safar Center for Resuscitation Research, University of Pittsburgh

9. Center for Neuroscience; Center for the Neural Basis of Cognition; Critical Care Medicine, University of Pittsburgh

10. Department of Pathology, University of Pittsburgh

11. Department of Human Genetics, University of Pittsburgh School of Public Health

Abstract

Traumatic brain injury (TBI) is a predisposing factor for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). Although defects in nucleocytoplasmic transport (NCT) is reported ALS and other neurodegenerative diseases, whether defects in NCT occur in TBI remains unknown. We performed proteomic analysis on Drosophila exposed to repeated TBI and identified resultant alterations in several novel molecular pathways. TBI upregulated nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) proteins as well as alter nucleoporin stability. Traumatic injury disrupted RanGAP1 and NPC protein distribution in flies and a rat model and led to coaggregation of NPC components and TDP-43. In addition, trauma-mediated NCT defects and lethality are rescued by nuclear export inhibitors. Importantly, genetic upregulation of nucleoporins in vivo and in vitro triggered TDP-43 cytoplasmic mislocalization, aggregation, and altered solubility and reduced motor function and lifespan of animals. We also found NUP62 pathology and elevated NUP62 concentrations in postmortem brain tissues of patients with mild or severe CTE as well as co-localization of NUP62 and TDP-43 in CTE. These findings indicate that TBI leads to NCT defects, which potentially mediate the TDP-43 pathology in CTE.

Funder

National Institute of Neurological Disorders and Stroke

Robert Packard Center for ALS Research, Johns Hopkins University

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3