The optineurin/TIA1 pathway inhibits aberrant stress granule formation and reduces ubiquitinated TDP-43

Taichi Kakihana; Masahiko Takahashi; Yoshinori Katsuragi; Shun-Ichi Yamashita; Junya Sango; Tomotake Kanki; Osamu Onodera; Masahiro Fujii

doi:10.1016/j.isci.2021.102733

The optineurin/TIA1 pathway inhibits aberrant stress granule formation and reduces ubiquitinated TDP-43

iScience. 2021 Jun 17;24(7):102733. doi: 10.1016/j.isci.2021.102733. eCollection 2021 Jul 23.

Authors

Taichi Kakihana¹, Masahiko Takahashi¹, Yoshinori Katsuragi¹, Shun-Ichi Yamashita², Junya Sango¹, Tomotake Kanki², Osamu Onodera³, Masahiro Fujii¹

Affiliations

¹ Division of Virology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
² Department of Cellular Physiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
³ Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.

Abstract

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease characterized by the formation of cytoplasmic ubiquitinated TDP-43 protein aggregates in motor neurons. Stress granules (SGs) are stress-induced cytoplasmic protein aggregates containing various neuropathogenic proteins, including TDP-43. Several studies have suggested that SGs are the initial site of the formation of pathogenic ubiquitinated TDP-43 aggregates in ALS neurons. Mutations in the optineurin (OPTN) and TIA1 genes are causative factors of familial ALS with TDP-43 aggregation pathology. We found that both OPTN depletion and ALS-associated OPTN mutations upregulated the TIA1 level in cells recovered from heat shock, and this upregulated TIA1 increased the amount of ubiquitinated TDP-43. Ubiquitinated TDP-43 induced by OPTN depletion was localized in SGs. Our study suggests that ALS-associated loss-of-function mutants of OPTN increase the amount of ubiquitinated TDP-43 in neurons by increasing the expression of TIA1, thereby promoting the aggregation of ubiquitinated TDP-43.

Keywords: Biological sciences; Cellular neuroscience; Molecular neuroscience.