Cited 4 time in webofscience Cited 4 time in scopus

Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin alpha 3

Title
Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin alpha 3
Authors
Park, Jeong HyangChung, Chang GeonPark, Sung SoonLee, DavinKim, Kyung MinJeong, YeonjinKim, EunSeonCho, JaeHoJeon, Yu-MiShen, C-K JamesKim, Hyung-JunHwang, DaeheeLee, Sung Bae
DGIST Authors
Lee, Sung Bae
Issue Date
2020-12
Citation
eLife, 9, e60132
Type
Article
Article Type
Article
Keywords
BINDING PROTEIN 43NUCLEAR IMPORTHEXANUCLEOTIDE REPEATRECEPTORALSSCLEROSISRNALOCALIZATIONDISEASEMECHANISMS
ISSN
2050-084X
Abstract
Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Here, we identified via FRAP and optogenetics cytosolic calcium as a key cellular factor controlling NCT of TDP-43. Dynamic and reversible changes in TDP-43 localization were observed in Drosophila sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin α3 pathway as a regulatory mechanism underlying NCT of TDP-43. In C9orf72 ALS fly models, upregulation of the pathway activity by increasing cytosolic calcium reduced cytoplasmic accumulation of TDP-43 and mitigated behavioral defects. Together, these results suggest the calcium-Calpain-A-Importin α3 pathway as a potential therapeutic target of ALS. © Park et al.
URI
http://hdl.handle.net/20.500.11750/12681
DOI
10.7554/eLife.60132
Publisher
eLife Sciences Publications Ltd
Related Researcher
  • Author Lee, Sung Bae Laboratory of Neurodegenerative Diseases and Aging
  • Research Interests Cellular mechanism of neurodegenerative diseases; Neuronal maintenance and remodeling; 퇴행성 뇌질환의 세포기전; 신경계 유지 및 리모델링 연구
Files:
Collection:
Department of Brain and Cognitive SciencesLaboratory of Neurodegenerative Diseases and Aging1. Journal Articles


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