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

Hsiang-Yu Chang, Shin-Chen Hou, Tzong- Der Way, Chi-Huey Wong and I-Fan Wang ()
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Hsiang-Yu Chang: Garage Brain Science
Shin-Chen Hou: Garage Brain Science
Tzong- Der Way: College of Life Sciences, China Medical University
Chi-Huey Wong: Genomic Research Center, Academia Sinica
I-Fan Wang: Garage Brain Science

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms3757

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