Huntington’s Disease Origin Revealed by Research

Devastating neurodegenerative illnesses such as Huntington’s, Alzheimer’s, and Parkinson’s are all linked to amyloid protein accumulation in the brain. Despite significant investment in research into the source and toxicity of amyloids, determining the first stage in development, as well as viable therapeutics, has remained elusive. Scientists at the Stowers Institute for Medical Research have discovered the structure of the initial phase in amyloid production, known as the nucleus, for Huntington’s disease for the first time. The discovery, published in eLife by Associate Investigator Randal Halfmann, Ph.D.’s group, presents a novel, radical technique for treating not only Huntington’s disease but potentially dozens of other amyloid-related disorders by 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,” said Halfmann. “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.”

Tej Kandola, Ph.D., and Shriram Venkatesan, Ph.D., co-first authors, discovered that the amyloid nucleus for huntingtin, the protein responsible for Huntington’s disease, originates within a single protein molecule.

Proteins are the factory workers of the cell, made up of unique sequences of 20 amino acids, which serve as their building blocks. Repeats of one of these amino acids, glutamine (abbreviated as Q), can be found in some proteins. Huntington’s disease and eight other disorders, generally known as “PolyQ diseases,” develop when certain proteins have an excessively long repetition. This, in turn, leads the proteins to fold into a certain form, resulting in a chain reaction that kills the cell.

For three decades, we’ve known that Huntington’s and related fatal diseases occur when proteins contain more than around 36 Qs in a row, causing them to form chains of proteins in the brain, but we didn’t know why,” said Halfmann. “We’ve now figured out what the first link in the chain looks like, and, in doing so, have discovered a new way to stop it.”

“I am, frankly, astonished that such an intuitive physical model of nucleation emerged despite the intrinsic complexity of the cellular environment,” said Professor Jeremy Schmit, Ph.D., from Kansas State University.

“I am truly excited by the intuition and the testable hypotheses that this work inspires.”

A paradigm change and a possible therapeutic strategy
These new findings could result in a paradigm shift in how we think about amyloids. The findings of this study imply that neuronal cell death is caused by the early committed steps of amyloid production, right after the nucleus develops.

In addition to discovering the essential structure that initiates polyQ amyloid formation, researchers discovered that it only occurs in isolated molecules of the protein. Clumping the proteins together in cells prevented the formation of amyloids entirely. This is a novel treatment approach that the team intends to investigate further in mice and brain organoids. There are several potential new treatments for Huntington’s disease revealed earlier.

A novel method
Distributed Amphifluoric Förster Resonance Energy Transfer (DAmFRET), a technology recently developed by the Halfmann Lab, demonstrates how a protein self-assembles in single cells. This approach proved critical for observing the rate-limiting amyloid-formation nucleation event.

“A key innovation was to minimize the volume of the reaction to such an extent that we can witness its stochasticity, or randomness, and then we tweak the sequence to figure out what is governing that,” said Halfmann.

The team was able to deduce the lowest structure that may produce amyloid by designing and testing specific patterns of Qs—a bundle of four strands, each with three Qs in specific locations. This small crystal inside a single protein molecule is the first step in a chain reaction that leads to illness.

“Prior work in test tubes supports a monomeric nucleus, but this model has been controversial,” said Halfmann. “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.”

Essentially, this work gives a molecular model for studying the structure of every amyloid nucleus. Furthermore, the link between aging and amyloids suggests that this technology may eventually reveal molecular pathways that underlie aging. The proactive strategy to preventing or delaying nucleation gives persons with pathologic PolyQ proteins hope.

“The emerging paradigm is that everything follows from a single event, a spontaneous change in protein shape,” said Halfmann. “That event ignites the chain reaction for amyloids that kill cells and may provide critical insight into how amyloids cause disease.”

Source Link