Researchers have long known that when a cell becomes cancerous, heat-shock protein 90 (Hsp90) helps it survive in its diseased state. Now a team of scientists led by Memorial Sloan-Kettering investigator Gabriela Chiosis has found that Hsp90 also enables the disease process in a group of neurodegenerative disorders marked by the accumulation of the protein Tau. The study, which illustrates that these two types of diseases are governed by a common principle, was published May 29 in the Proceedings of the National Academy of Sciences. [PubMed Abstract]
Normally, Tau resides on a docking site within a cell. In certain neurodegenerative diseases, including Alzheimer's disease, genetic and cellular mechanisms modify Tau, dislodging it from its docking site. Over time, Tau accumulates into toxic aggregates, dense protein clusters that cells cannot remove. As this waste builds up, a normally functioning nerve cell (neuron) is transformed into a defective one, and eventually the neuron dies.
"In both cancer and neurodegenerative diseases, Hsp90 facilitates the accumulation of cellular misprocessing that allows disease to blossom," Dr. Chiosis said. "In cancer, the outcome is increased proliferation of diseased cells. In neurodegenerative diseases, it leads to the ultimate demise of the neuron."
Studying neurons in both cell cultures and mouse models that had a mutant version of Tau, the researchers found that Hsp90 maintained the diseased Tau, allowing it to aggregate and kill the neuron. However, inhibiting Hsp90 depleted the neuron of the diseased Tau and restored normal neuron functioning.
"New treatments that target Hsp90 have been proposed for cancer, and some are currently in Phase I and Phase II clinical trials," said Dr. Chiosis. "Because of this study, we may be able to propose similar treatments for some neurodegenerative diseases -- treatments that were never considered before."
