ATTEC: a potential new approach to target proteinopathies

Area of Science:

• Molecular Biology
• Neuroscience
• Drug Discovery

Background:

• Aberrant protein accumulation causes diseases, making protein level reduction a therapeutic strategy.
• Huntington's disease (HD) is characterized by the cytotoxic mutant Huntingtin (mHTT) protein.
• Autophagy, mediated by LC3, is a cellular process for degrading damaged components.

Purpose of the Study:

• To test the hypothesis that compounds targeting both disease proteins and LC3 can induce autophagic degradation.
• To validate the autophagosome-tethering compound (ATTEC) concept for treating Huntington's disease.
• To identify novel compounds for targeting mHTT and potentially other polyglutamine expansion diseases.

Main Methods:

• Designed and employed a small-molecule microarray screening to identify compounds binding to mHTT and LC3.
• Tested identified compounds for their ability to target mHTT to phagophores for degradation.
• Evaluated compound efficacy in cellular and in vivo models of Huntington's disease (flies and mice).

Main Results:

• Identified four compounds that specifically bind to mHTT and LC3, but not wild-type HTT.
• Demonstrated that these ATTECs effectively promote autophagic degradation of mHTT without affecting normal HTT levels.
• Observed rescue of HD-relevant phenotypes in cellular and animal models, with compounds targeting expanded polyQ stretches.

Conclusions:

• Provided the first validation of the ATTEC strategy for lowering mHTT levels in Huntington's disease.
• Established ATTECs as a promising therapeutic entry point for HD and other diseases caused by expanded polyglutamine proteins.
• Highlighted the potential of targeting protein-LC3 interactions for disease treatment.