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Researchers here demonstrate a proof of principle for an interesting approach to tackling the aggregation of damaged, altered, or misfolded proteins that is a feature of most neurodegenerative conditions. They target the mutant huntingtin protein, which is probably an easier task than targeting, say, a misfolded protein with a normal sequence. The basic idea is to deploy a linking molecule that binds to the problem protein with high specificity, and also binds to an essential component of autophagy – in this case LC3B, involved in the generation of autophagosomes responsible for carrying materials to lysosomes. This ensures that the whole linked set of molecules is dragged into an autophagosome and transported to a lysosome where it is broken down and recycled.
Several neurodegenerative diseases involve the slow accumulation of a misfolded protein in neurons over many years. The proteins involved in these diseases might differ, but the result is similar – eventually, the neurons die from the build-up of toxic misfolded proteins. Scientists have long been searching for ways to reduce the levels of the disease-driving proteins without also clearing their wild-type counterparts, which typically have myriad crucial functions. Researcher snow show that this can be accomplished using compounds that interact specifically with both the misfolded part of the protein and the neuron’s protein-clearance machinery.
The researchers chose to focus on Huntington’s disease, which is caused by an abnormally long stretch of glutamine amino-acid residues in the huntingtin (HTT) protein. This expanded polyglutamine tract causes HTT to misfold. Cells are able to degrade the mutant huntingtin (mHTT) through autophagy – a clearance mechanism that involves engulfment of proteins by a vesicle called the autophagosome. Researchers hypothesized that compounds that bind to both the mutant polyglutamine tract and the protein LC3B, which resides in the autophagosome, would lead to engulfment and enhanced clearance of mHTT. But no such compounds had been reported. The authors therefore conducted small-molecule screens to identify candidate compounds.
Researchers initially identified two candidates, dubbed 10O5 and 8F20. These compounds had been shown to inhibit, respectively, the activity of the cancer-associated protein c-Raf and kinesin spindle protein (KSP), which has a key role in the cell cycle. The team found that 10O5 and 8F20 were able to clear mHTT independently of their effects on these other proteins. The researchers showed that the regions of 10O5 and 8F20 that interacted with mHTT and LC3B in the screen shared structural similarities. Next, they screened for compounds that shared these structural properties but were structurally distinct. This led them to discover two more compounds, AN1 and AN2, that link mHTT to LC3B and thereby selectively reduce levels of mHTT.
Researchers validated their discovery by showing that the four compounds reduced levels of the full-length mHTT protein (not just the protein fragment used in the screen). The compounds lowered levels of mHTT both in vitro – in mouse neurons and neurons derived from the biopsied skin cells of people with Huntington’s disease – and in vivo, in mouse and fly models of the disease.
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