In a surprise discovery that topples decades of thinking on how the body fixes proteins, scientists have opened up new doors for protein-folding treatments, moving one step closer to preventing Alzheimer’s and other protein-linked brain diseases.1
“This finding provides a whole other outlook on protein-folding diseases; a new way to go after them,” Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair of Stem Cell Research in the Department of Molecular and Cell Biology and Howard Hughes Medical Institute investigator at the University of California, Berkeley, said in a news release.
Here’s how it works: As those in medical assistant programs may know, proteins must fold into the right 3-D structure to work, and the body produces a plethora of chaperone molecules to refold misfolded proteins. Heat shock further increases the number of these chaperones.2 The research from the University of California-Berkley and University of Michigan shows that, equally important, heat shock also boosts a protein that stabilizes actin, the building block of the cytoskeleton.1
In the cell, there are at least 350 separate molecular chaperones patrolling around to refold misfolded proteins. Misfolded proteins occur when the protein follows the wrong folding pathway or energy-minimizing tunnel. As millions and millions of copes of each protein are made during our lifetimes, a protein could become a toxic configuration.3 When misfolded proteins grow out of control, they have been associated with neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s. Importantly, heat is one of the major antagonists to healthy proteins.1
Focusing on the wrong function
For more than 30 years, it was believed that when cells undergo heat shock, such as in fever, they create a protein called heat shock factor-1 (HSF-1), which triggers a cascade of events that send more chaperones to refold unraveling proteins. Proteins under pressure could kill the cell. However, by binding to promoters upstream of the 350-plus chaperone genes, HSF-1 boosts the genes’ activity and launches an army of chaperones.1
As a result, scientists looked for ways to artificially boost HSF-1 in order to lower the protein plaques and tangles that ultimately kill brain cells. Such boosters have extended lifespan in lab animals but greatly increased the rates of cancer.
Now, Dillin and his colleagues found that HSF-1 plays a bigger role than just triggering the release of chaperones – it also stabilizes the cell’s cytoskeleton, which is the highway that transports necessary supplies – including healing chaperones – around the cell. More specifically, HSF-1 up-regulates another gene called pat-10, which produces a protein that stabilizes actin. Actin then cements the cytoskeleton as a more secure structure.
“We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington’s, we should be looking for ways to make the actin cytoskeleton better,” Dillin said. The Berkley scientist believe this might avoid the cancerous side effects of increasing HSF-1.
Dillin and researchers were able to cure worms that had been altered to express the Huntington’s disease gene, and also extend the lifespan of normal worms. They found that injecting animals with HSF-1 both raises their tolerance of heat stress and lengthens their lifespan.
Heat shock like a besieged country
Dillin said heat shock can be compared to a country under attack. In a war, an aggressor cuts off all communications and impedes transportation, such as roads, train and bridges. This prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, restricting the chaperone “doctors” from reaching the misfolded proteins.1
“We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors,” Dillin told the source.
Previously, the focus was on the wrong detail, the wrong function. When Dillin had first explained his suspicions to co-workers, it went against the grain. The idea was contradictory to everything that came before it, but once he garnered enough evidence to overturn previous findings, other members in the protein-folding community admitted it made perfect sense. Dillin and his team now suspect that HSF-1’s main function is to protect the actin cytoskeleton.
The Scripps Research Institute and Genentech Inc., will publish their results in the journal Science. Down the road, professionals who attended medical assistant schools may help administer potential treatments to prevent protein misfolding and its associated diseases, including Alzheimer’s, Huntington’s and Parkinson’s.1
1Sanders, R. (2014, October 16). New front in war on Alzheimer’s & other protein folding diseases. Retrieved October 17, 2014, from http://newscenter.berkeley.edu/2014/10/16/new-front-in-war-on-alzheimers-other-protein-folding-diseases/
2New front in war on Alzheimer’s, other protein-linked brain diseases. (2014, October 1). Retrieved October 17, 2014, from http://www.sciencedaily.com/releases/2014/10/141016143658.htm
3Reynaud, E. (2010, January 1). Protein Misfolding and Degenerative Diseases. Retrieved October 17, 2014, from http://www.nature.com/scitable/topicpage/protein-misfolding-and-degenerative-diseases-14434929