Devastating neurodegenerative diseases like Huntington’s, Alzheimer’s, and Parkinson’s are all associated with protein deposits in the brain, known as amyloid. Despite extensive research investment into the cause and toxicity of amyloids, deciphering the first step in formation along with effective therapies has remained elusive.
For the first time, scientists at the Stowers Institute for Medical Research have uncovered the structure of the first step in amyloid formation, called the nucleus, for Huntington’s disease. The study published in eLife on June 13, 2023, from the lab of Associate Investigator Randal Halfmann, Ph.D., proposes a new, radical method for treating not only Huntington’s but potentially dozens of other amyloid-associated diseases—preventing the initial, rate-limiting step from occurring.
This is the first time anyone has experimentally determined the structure of an amyloid nucleus even though most major neurodegenerative diseases are associated with amyloids. One of the big mysteries of Huntington’s, Alzheimer’s, and ALS is why disease coincides with amyloid, yet the amyloids themselves are not the main culprits.Randal Halfmann
Co-first authors Tej Kandola, Ph.D., and Shriram Venkatesan, Ph.D., uniquely identified the structure of the amyloid nucleus for huntingtin, the protein responsible for Huntington’s disease, discovering that the nucleus forms within a single protein molecule.
These new findings are potentially a paradigm shift for how we view amyloids. The results from this research suggest that it is the early committed steps of amyloid formation, right after the nucleus forms, that cause neuronal cell death.
Prior work in test tubes supports a monomeric nucleus, but this model has been controversial. We now have strong evidence that 36 Qs is the critical number for nucleation to happen in single protein molecules, and moreover, that this is how it happens inside living cells.Randal Halfmann
In essence, this work provides a molecular model to investigate the structure of any amyloid nucleus. Additionally, the correlation between aging and amyloids suggests that this method may ultimately uncover molecular mechanisms that cause aging. The preemptive approach to eliminate or at the very least to delay nucleation provides hope for people with pathologic PolyQ proteins.
The emerging paradigm is that everything follows from a single event, a spontaneous change in protein shape. That event ignites the chain reaction for amyloids that kill cells and may provide critical insight into how amyloids cause disease.Randal Halfmann
About the Stowers Institute for Medical Research
Founded in 1994 through the generosity of Jim Stowers, founder of American Century Investments, and his wife, Virginia, the Stowers Institute for Medical Research is a non-profit, biomedical research organization with a focus on foundational research. Its mission is to expand our understanding of the secrets of life and improve life’s quality through innovative approaches to the causes, treatment, and prevention of diseases.
The Institute consists of 20 independent research programs. Of the approximately 500 members, over 370 are scientific staff that include principal investigators, technology center directors, postdoctoral scientists, graduate students, and technical support staff. Learn more about the Institute at www.stowers.org and about its graduate program at www.stowers.org/gradschool.
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