Publication date: Nov 02, 2019
They’ve identified molecules that can link the damaged form of the protein to a system that cells use to target proteins for digestion and recycling.
When being translated into a protein, the bases of DNA are read in sets of three, with each triplet coding for a different amino acid (or telling the cell to stop translating).
While it’s not clear exactly what the defective form of the protein does at a biochemical level, it’s clear that it’s toxic to nerve cells.
The defective protein is similar enough to the normal one that you can’t simply target it-it’s identical except for having more of just one of its amino acids.
To do so, the team created an array of about 3,400 chemicals and then identified ones that stuck to the repeated amino acids of the defective protein.
They tested these and showed that they specifically interacted with the defective version of the Huntington’s gene, not the normal one (they also confirmed it didn’t stick to proteins in general by trying a couple of random ones).
And, as hoped for, when given to cultured nerve cells, the chemicals reduced the levels of the defective protein, not the normal one.
So, in order to get something specific to the Huntington’s protein, the researchers next looked at the structures of the two successful chemicals and identified a number of additional chemicals that shared some of the key features of these two.
They identified two additional chemicals that could target the defective Huntington’s protein for destruction but were more specific to it.
Tests also confirmed that the chemicals had very little effect on other proteins in the cell, indicating that they weren’t causing a general increase in autophagy.
As mentioned above, several forms of ataxia are caused by an expansion of the same amino acid that’s duplicated in the Huntington’s disease gene, and so these may undergo the same sort of interactions with these two chemicals.