# Chemical Targeting of the ATXN1 aa99–163 Interaction Site Suppresses polyQ-Expanded Protein Dimerization

## TL;DR

A chemical compound was found to block harmful protein interactions in a neurodegenerative disease called SCA1, potentially offering a new treatment.

## Contribution

Identification of a specific protein interaction site and a compound that inhibits aggregation in SCA1.

## Key findings

- Amino acids 99–163 in ATXN1 are critical for dimerization and interaction with MED15.
- Compound 5755483 inhibits both ATXN1-MED15 interaction and polyQ protein dimerization.
- Targeting this domain may prevent protein aggregation in SCA1.

## Abstract

Spinocerebellar ataxia
type 1 (SCA1) is a neurodegenerative disease
caused by the expansion of a polyglutamine (polyQ) tract in the ATXN1
protein. This expansion is thought to be responsible for the gradual
aggregation of the mutant protein, which is associated with increased
cytotoxicity and neuronal cell death. Apart from the polyQ tract,
other domains in ATXN1 are also involved in the initial events of
protein aggregation, such as a dimerization domain that promotes protein
oligomerization. ATXN1 interacts with various proteins; among them,
MED15 significantly enhances the aggregation of the polyQ-expanded
protein. Therefore, we set to identify the interaction site between
ATXN1 and MED15 and assess whether its chemical targeting would affect
polyQ protein aggregation. First, we predicted the structures of ATXN1
and MED15 and simulated their interaction. We experimentally validated
that amino acids (aa) 99–163 of ATXN1 and aa548–665
of MED15 are critical for this protein–protein interaction
(PPI). We also showed that the aa99–163 domain in ATXN1 is
involved in the dimerization of the mutant isoform. Targeting this
domain with a chemical compound identified through virtual screening
(Chembridge ID: 5755483) inhibited both the interaction of ATXN1 with
MED15 and the dimerization of polyQ-expanded ATXN1. These results
strengthen our assumption that the aa99–163 domain of ATXN1
may be involved in polyQ protein aggregation and highlight compound
5755483 as a potent first-in-class therapeutic agent for SCA1.