Mark Ciardiello

Professor Janet Rinehart-Kim

Biology 294

16 October 2023

Huntington’s spreads like wildfire

            NPR made an article regarding how Huntington’s disease spreads within the brain. They had Randal Halfmann on their show, where he discussed how the neurodegenerative disease’s symptoms are caused by a misfolding of the PolyQ protein. This protein exists naturally, but when in the misfolded form, the proteins clump together and begin to form plagues. Once one molecule of misfolded PolyQ forms, the likelihood of more PolyQ proteins clumping together increases. Halfmann’s team discovered all this through essentially trial and error, manually modifying PolyQ until one of the forms showed to disrupt neuron activity. His team also found ways to combat PolyQ from clumping on itself whenever this misfolding occurs. While simple in concept, the team flushed specific proteins through the affect area, preventing the PolyQ clump from spreading elsewhere. The end goal for Halfmann is to create a drug that could mimic or do exactly what his team did to prevent clumps from spreading further like wildfire. The greater part of his team’s findings is that Huntington’s disease isn’t the only neurodegenerative disease that is caused by plaque buildup. Drugs used to target plaque build up didn’t appear to be effective, but drugs that targeted the clumps of PolyQ did, confirming the results from Halfmann’s team (1).

            The validity of NPR’s article about Huntington’s disease should be seen as accurate. Looking at an article from PubMed on polyglutamine repeats in neurodegenerative diseases, it can be confirmed that polyglutamine (PolyQ), specifically expanded CAG domains, are the primary drivers of neurodegeneration. The PubMed article further explained that the problematic PolyQ also creates many downstream effects, making it extremely hard to find therapies that effectively prevented or cure a patient from neurodegeneration (2).

             The relation of PolyQ protein misfolding to genetics is duplications in the coding of the protein. What causes the protein to misfold is an expanded CAG domain, resulting from repeating sequences of CAG. The modification of glutamine producing genes results in these expanded PolyQ proteins that are more subjected to folding on themselves, causing the problems describe in the NPR article where the misfolded proteins pile on themselves into these toxic clumps.

Citations

1. Hamilton J. “Huntington’s spreads like ‘fire in the brain.’ Scientists says they’ve found the spark.” NPR; https://www.npr.org/sections/health-shots/2023/06/19/1182881226/huntingtons-spreads-like-fire-in-the-brain-alzheimers-parkinsons#:~:text=’%20Scientists%20say%20they’ve%20found%20the%20spark,-Listen%C2%B7%203%3A39&text=In%20Huntington’s%20disease%2C%20proteins%20form%20toxic%20clumps%20that%20kill%20brain%20cells.,-Stowers%20Institute%20for&text=Diseases%20like%20Alzheimer’s%2C%20Parkinson’s%2C%20and,brain%20like%20a%20forest%20fire. (2023).

2. Lieberman AP, Shakkottai VG, Albin RL. Polyglutamine Repeats in Neurodegenerative Diseases. PubMed; https://doi: 10.1146/annurev-pathmechdis-012418-012857 (2019).