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

iScience

Tomotake Kanki¹  Shun-Ichi Yamashita¹  Osamu Onodera²  Yoshinori Katsuragi³  Taichi Kakihana³  Masahiro Fujii³  Masahiko Takahashi³  Junya Sango³ 

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

关键词: Biological sciences;    Molecular neuroscience;    Cellular neuroscience;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown