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New Huntington’s molecular model reveals the start of the disease

Huntington's disease


A new study may represent a “paradigm shift” in understanding how toxic proteins behind neurological diseases begin to form.


It offers a new molecular model for investigating the structure of any amyloid nucleus – as well as  fresh hope for sufferers of conditions like Huntington’s disease and Alzheimer’s.


Published on the eLife platform, the research suggests that the huntingtin protein folding which causes Huntington’s starts with a change in shape within a single protein molecule.


It also found that the change only occurs in isolated huntingtin molecules, and that pre-emptively clumping the proteins together in cells may stop amyloids forming altogether.


This last discovery could open up an admittedly radical” new way of treating Huntington’s and potentially other amyloid-associated diseases, such as Alzheimer’s, by preventing the initial rate-limiting step from occurring. Such a ‘clumping’ approach could be tested in experiments on mice and brain organoids soon.


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 associate investigator Randal Halfmann, of the Stowers Institute for Medical Research in Kansas City.


“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.”


In order to observe the rate-limiting nucleation event behind the formation of amyloids, the research team developed a novel technique called Distributed Amphifluoric Förster Resonance Energy Transfer (DAmFRET) – using a photoconvertible fusion tag and high throughput flow cytometry “to treat living cells as femtoliter-volume test tubes.” This gave them “the large numbers of independent reaction vessels of exceptionally small volume that are required to discriminate independent nucleation events under physiological conditions.”


“A(nother) 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,” added Halfmann.


Huntington’s and eight other neurological conditions, collectively called ‘PolyQ diseases’,  are caused when glutamine (Q) amino acid sequences within protein molecules repeatedly create overlong ‘tails of approximately 36 Qs in a row. This causes the proteins to fold into structures that somehow start the process of killing neuronal cells – a reaction that the Stowers Institute study gives us a first detailed look at.


“We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position,” the Stowers researchers state.


“We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains.


“Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei.”


According to Halfmann, the breakthrough supports and clarifies the previously controversial view that the disease process begins in a ‘monomeric nucleus’ - explained as a tiny crystal in a single molecule of the Poly Q protein that could trigger a chain reaction leading to Huntington’s disease. He also argues that it disproves the more popular idea of nucleation happening in an oligomer or condensate of polyQ.


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


The group also speculated that its clumping approach to treatment could work more effectively than existing methods, adding: “Current therapeutic efforts focused on lowering the levels of mutant huntingtin have not been successful.


“As an admittedly radical alternative, we suggest that therapies designed to (further) oligomerize huntingtin preemptively will delay nucleation and thereby decelerate the disease.”





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