A newest research provides an explanation for why cellular quality control process fails to repair or remove misfolded proteins in Huntington’s disease. The findings could lead to novel ways to treat the devastating disease. The study appears in Nature Communications, and study researchers include Rocio Gomez-Pastor, Eileen Burchfiel, Daniel Neef, Alex Jaeger, Spencer McKinstry, Argenia Doss, Alejandro Aballay, Donald Lo, Christopher Ross, Cagla Eroglu and Dennis Thiele of Duke University School of Medicine, Elisa Cabiscol of Universitat de Lleida, and Sergey Akimov of Johns Hopkins University School of Medicine. Normally cellular quality control process helps fix or get rid of misfolded proteins, avoiding the harmful effects of these proteins. Misfolded proteins are typically nonfunctional, and may accumulate to a toxic level that compromises the cellular protein homeostasis balance and jeopardizes cell viability. So the cells' ability to contend with a continuous stream of misfolded proteins is important for cell survival. Chaperones -- part of cellular quality control mechanism -- are a class of proteins that assist the folding or unfolding and the assembly or disassembly of other proteins. Under normal circumstances, chaperones help ensure that proteins fold into three-dimensional structures properly. In Huntington's patients, chaperone proteins are significantly scarce. To date, why this occurs remains unclear. Huntington's is a neurodegenerative disease that occurs when the Htt protein folds into an incorrect three-dimensional shape. The misfolded protein is nonfunctional and accumulates in the nerve system, eventually impairing nerve cells that control movement and thought. The aim of the new study is elucidate what disrupts this protective mechanism in Huntington's. The researchers looked at chaperones and found that a protein critical for regulating chaperone production, HSF1, was degraded in cells and mice expressing mutant Htt, in neurons derived from human Huntington's disease induced pluripotent stem cells, and in brain samples from Huntington's patients. The degradation was caused by increased levels of another molecule called CK2. Because of HSF1 degradation, nerve cells became unable to generate enough chaperones and could eventually die. The researchers also found that blocking CK2 restored the levels of chaperones, which in turn protected healthy neurons and preserved muscle mass. Muscle loss is common among Huntington's patients, and is one of the major causes of mortality. Together, the study revealed a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting in Huntington's. Furthermore, the results are consistent with the findings of previous studies. Some earlier studies have shown that activating HSF1 is a way to protect neurons from stress and damage in Huntington's. In addition, Cusabio provides HSF1 and CK2 related proteins and antibodies and Recombinant PTPRA.
