A strategy to selectively remove mutant proteins could combat neurodegeneration, according to new research, which showed this could be accomplished by using compounds that interact with the misfolded part of the protein and the neuron’s protein-clearance machinery.

Many neurodegenerative diseases involve the slow accumulation of a misfolded protein in neurons over many years, leading to the death of neurons from the build-up of toxic proteins. Scientists have long been searching for ways to reduce the levels of the disease-driving proteins without also clearing their wild-type counterpart.

Zhaoyang Li and a team of researchers focused on the Huntington’s disease, caused by an abnormally long stretch of glutamine amino-acid residues in the huntingtin (HTT) protein. This expanded polyglutamine tract causes HTT to misfold.

Affected individuals typically carry one copy of the HTT gene that encodes the mutant protein, and one allele that encodes a protein with the normal-length glutamine tract. Cells are able to degrade the mutant huntingtin (mHTT) through autophagy2 — a clearance mechanism that involves the engulfment of proteins.

The study 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.

So, Li and colleagues conducted small-molecule screens to identify candidate compounds and used wild-type HTT in a counter-screen to rule out compounds that bind to the normal version of the protein.

They initially identified two candidates, dubbed 10O5 and 8F20. These compounds had been shown to inhibit the activity of the cancer-associated protein c-Raf and kinesin spindle protein (KSP), which has a key role in the cell cycle. They 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 the two candidates 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 from other c-Raf and KSP inhibitors. This led them to discover two more compounds, AN1 and AN2, that link mHTT to LC3B and thereby selectively reduce levels of mHTT.

The compounds leave levels of wild-type HTT unchanged. This is crucial because HTT has multiple neuronal functions, both during embryonic development and after birth. Existing mHTT-lowering strategies typically affect both HTT alleles, which is not ideal.

The authors found encouraging evidence that the compounds could produce functional improvements in models of Huntington’s disease across three species. Patient-derived neurons treated with each of the compounds showed significantly less shrinkage, degeneration of neuronal projections and cell death than was seen in untreated neurons.

At the same time, flies that model Huntington’s disease and were treated with the compounds recovered climbing ability and survived longer than did untreated counterparts. Also, treated mice that model Huntington’s disease showed improvements in three motor tests, compared with untreated mice.

Looking ahead, there are several research paths. First, establishing the mechanism by which Li and colleagues’ compounds recognize proteins with expanded polyglutamine tracts but spare normal proteins. Then, testing the compounds in other models of polyglutamine disorders and assessing their effects.