Some neurodegenerative diseases or conformational diseases are caused by aberrant protein misfolding and aggregation. Polyglutamine (polyQ) expansion can make the disease-related proteins readily misfolded and form insoluble aggregates or inclusions. However, how the protein aggregates lead to cellular dysfunction and cytotoxicity remains elusive.
Recently, a research team led by Dr. HU Hongyu from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences , Chinese Academy of Sciences, revealed that aggregation of polyQ-expanded ataxin-3(Atx3) sequesters its specific interacting partners into inclusions and thus impairs the cellular function of these essential proteins.
YANG Hui and her colleagues in Dr. HU’s lab found that aggregation of polyQ -expanded Atx3 sequesters P97/VCP and ubiquitin conjugates into the protein inclusions through specific interactions both in vitro and in cell. This specific sequestration impairs the normal cellular function of P97/VCP in down-regulating neddylation. Biophysical study revealed that aggregation of the polyQ expansion in Atx3 does not affect the conformation of its surrounding regions and the interaction affinities with its interacting partners. Thus, the direct effect of polyQ expansion is to entice the protein prone to aggregation and alter its state from soluble to insoluble, and simultaneously sequesters its interacting partners into the inclusions during aggregation process. Based on their findings, the authors proposed a loss-of-function pathology that polyQ aggregates cause cellular dysfunction and cytotoxicity by deteriorating the interacting partners in cell, which will be helpful for deciphering pathologies of the neurodegenerative diseases and discovering pharmaceutical therapies.
This work entitled “Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: Implication in a loss-of-function pathology” was published online in Scientific Reports on September 18, 2014. This work was supported by the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Chinese Academy of Sciences.
AUTHOR CONTACT:
HU Hongyu
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences,
Shanghai, China
Phone: 86-21-54921121;
E-mail: hyhu@sibcb.ac.cn
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