Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

• Published in: Nature communications Vol. 4; no. 1; p. 2757
• Main Authors: Chang, Hsiang-Yu, Hou, Shin-Chen, Way, Tzong-Der, Wong, Chi-Huey, Wang, I-Fan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2013; Nature Publishing Group
• Subjects: 13/44; 14/1; 14/19; 14/34; 14/35; 14/63; 38/109; 631/80/470/1981; 631/80/470/2284; 692/420; 692/699/375/365; 82/51; 96/2; Cell Death; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Image Processing, Computer-Assisted; multidisciplinary; Oxidative Stress; Reactive Oxygen Species; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3757

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. Misfolding and aggregation of TAR DNA-binding protein 43 is implicated in various neurodegenerative diseases. Chang et al . show that aggregation of this protein is regulated by heat-shock proteins, which act to reduce the amount of pathological protein aggregates.