Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation.
Conformational disorders are involved in various neurodegenerative diseases. Reactive oxygen species (ROS) are the major contributors to neurodegenerative disease; however, ROS that affect the structural changes in misfolded disease proteins have yet to be well characterized. Here we demonstrate that the intrinsic propensity of TDP-43 to aggregate drives the assembly of TDP-43-positive stress granules and soluble toxic TDP-43 oligomers in response to a ROS insult via a disulfide crosslinking-independent mechanism. Notably, ROS-induced TDP-43 protein assembly correlates with the dynamics of certain TDP-43-associated chaperones. The heat-shock protein (HSP)-90 inhibitor 17-AAG prevents ROS-induced TDP-43 aggregation, alters the type of TDP-43 multimers and reduces the severity of pathological TDP-43 inclusions. In summary, our study suggests that a common mechanism could be involved in the pathogenesis of conformational diseases that result from HSP dysregulation.
1] Garage Brain Science, Taichung 413, Taiwan [2] Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 404, Taiwan.
Hsiang-Yu
HY
Chang
Shin-Chen
SC
Hou
Tzong-Der
TD
Way
Chi-Huey
CH
Wong
I-Fan
IF
Wang
D016923:Cell Death; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D018384:Oxidative Stress; D017382:Reactive Oxygen Species
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species