Cytosolic calcium regulates cytoplasmic accumulation of tdp-43 through calpain-a and importin α3

Jeong Hyang Park, Chang Geon Chung, Sung Soon Park, Davin Lee, Kyung Min Kim, Yeonjin Jeong, Eun Seon Kim, Jae Ho Cho, Yu Mi Jeon, Hyung Jun Kim, Daehee Hwang, Sung Bae Lee, Che Kun James Shen

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article numbere60132
Pages (from-to)1-31
Number of pages31
JournaleLife
Volume9
DOIs
Publication statusPublished - Dec 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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