A study at Northwestern University by Dr. Richard Morimoto and colleagues shows that celastrol, a natural compound derived from the celastracaeae plant, has potential to treat Huntington's Disease. Celastrol has been safely used for many years in Chinese medicine. 26 different labs collaborated to screen small molecules that 'suppress properties associated with the expression of mutant Huntingtin." 286 promising compounds were isolated for a second screening using human cells to see if any increased the expression of heat shock protein 70. Five laboratories, each using a somewhat different method for screening, independently identified celastrol.
Heat shock protein 70 has been found to arrest neurodegeneration in a fruitfly model. Heat shock proteins got their name because they are produced when cells are stressed by heat or toxins; however, they have a maintenance role in cells as well, helping newly made proteins to fold properly (their chaperone function) and carrying old ones off for degradation.
Celastrol was found to induce heat shock protein 70 as well as 40 and 27 in a variety of cell types, including neurons. It also was found to be cytoprotective, inhibiting apoptosis (cell death) under conditions of severe stress. Because of these exciting results, research with the Bates HD mice will be starting soon. This is clearly a compound to watch.
-- Marsha L. Miller, Ph.D.
Dr. Richard I. Morimoto"We expect to do celastrol trials in mice by the beginning of the year with Gill Bates in London."
|Dr. Richard I. Morimoto|
Celastrols as inducers of the heat shock response and cytoprotection
Alterations in protein folding and the regulation of conformational states have become increasingly important to the functionality of key molecules in signaling, cell growth, and cell death. Molecular chaperones, because of their properties in protein quality control, afford conformational flexibility to proteins and serve to integrate stress-signaling events that influence aging and a range of diseases including cancer, cystic fibrosis, amyloidoses, and neurodegenerative diseases. We describe here characteristics of celastrol, a quinone methide triterpene and an active component from Chinese herbal medicine identified in a screen of bioactive small molecules, that activates the human heat shock response. From a structure/function examination, the celastrol structure is remarkably specific and activates the heat shock transcription factor HSF1 with kinetics similar to those of heat stress, as determined by the induction of HSF1 DNA binding, hyperphosphorylation of HSF1, and expression of chaperone genes. Celastrol can activate heat shock gene transcription synergistically with other stresses and exhibits cytoprotection against subsequent exposures to other forms of lethal cell stress. These results suggest that celastrols exhibit promise as a new class of pharmacologically active regulators of the heat shock response.
Source: J Biol Chem. 2004 Oct 26