Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology
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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
eLife Sciences Publications Ltd
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/90b066bb55a346c988f950c0e2c8e585 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:90b066bb55a346c988f950c0e2c8e585 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:90b066bb55a346c988f950c0e2c8e5852021-11-16T14:22:12ZTraumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology10.7554/eLife.675872050-084Xe67587https://doaj.org/article/90b066bb55a346c988f950c0e2c8e5852021-06-01T00:00:00Zhttps://elifesciences.org/articles/67587https://doaj.org/toc/2050-084XTraumatic 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.Eric N AndersonAndrés A MoreraSukhleen KourJonathan D CherryNandini RameshAmanda GleixnerJacob C SchwartzChristopher EbmeierWilliam OldChristopher J DonnellyJeffrey P ChengAnthony E KlineJulia KoflerThor D SteinUdai Bhan PandeyeLife Sciences Publications Ltdarticleneurodegenerationamyotrophic lateral sclerosischronic traumatic encephalopathyTDP-43MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
neurodegeneration amyotrophic lateral sclerosis chronic traumatic encephalopathy TDP-43 Medicine R Science Q Biology (General) QH301-705.5 |
| spellingShingle |
neurodegeneration amyotrophic lateral sclerosis chronic traumatic encephalopathy TDP-43 Medicine R Science Q Biology (General) QH301-705.5 Eric N Anderson Andrés A Morera Sukhleen Kour Jonathan D Cherry Nandini Ramesh Amanda Gleixner Jacob C Schwartz Christopher Ebmeier William Old Christopher J Donnelly Jeffrey P Cheng Anthony E Kline Julia Kofler Thor D Stein Udai Bhan Pandey Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology |
| description |
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. |
| format |
article |
| author |
Eric N Anderson Andrés A Morera Sukhleen Kour Jonathan D Cherry Nandini Ramesh Amanda Gleixner Jacob C Schwartz Christopher Ebmeier William Old Christopher J Donnelly Jeffrey P Cheng Anthony E Kline Julia Kofler Thor D Stein Udai Bhan Pandey |
| author_facet |
Eric N Anderson Andrés A Morera Sukhleen Kour Jonathan D Cherry Nandini Ramesh Amanda Gleixner Jacob C Schwartz Christopher Ebmeier William Old Christopher J Donnelly Jeffrey P Cheng Anthony E Kline Julia Kofler Thor D Stein Udai Bhan Pandey |
| author_sort |
Eric N Anderson |
| title |
Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology |
| title_short |
Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology |
| title_full |
Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology |
| title_fullStr |
Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology |
| title_full_unstemmed |
Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology |
| title_sort |
traumatic injury compromises nucleocytoplasmic transport and leads to tdp-43 pathology |
| publisher |
eLife Sciences Publications Ltd |
| publishDate |
2021 |
| url |
https://doaj.org/article/90b066bb55a346c988f950c0e2c8e585 |
| work_keys_str_mv |
AT ericnanderson traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT andresamorera traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT sukhleenkour traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT jonathandcherry traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT nandiniramesh traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT amandagleixner traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT jacobcschwartz traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT christopherebmeier traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT williamold traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT christopherjdonnelly traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT jeffreypcheng traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT anthonyekline traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT juliakofler traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT thordstein traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology AT udaibhanpandey traumaticinjurycompromisesnucleocytoplasmictransportandleadstotdp43pathology |
| _version_ |
1718426371452043264 |