R406 and its structural analogs reduce SNCA/α-synuclein levels via autophagic degradation

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Parkinson disease (PD) is characterized by Lewy bodies, primarily composed of alpha-synuclein (SNCA) aggregates.
• Reducing SNCA protein levels is a potential therapeutic strategy to slow PD progression.

Purpose of the Study:

• To identify compounds that enhance the autophagic degradation of SNCA.
• To investigate the mechanism by which these compounds reduce SNCA levels.

Main Methods:

• Small molecule microarray (SMM)-based screening was used to identify compounds.
• Autophagy-dependent degradation was validated using gene knockdown (ATG5) and an autophagy inhibitor (chloroquine).
• Cellular and organoid models of PD were used to assess the efficacy of the identified compound.

Main Results:

• The compound R406 was identified and shown to decrease SNCA protein levels via autophagy.
• R406 reduced phosphorylated SNCA (p-S129-SNCA) levels in cellular models and rescued neuron degeneration.
• R406 alleviated PD-relevant phenotypes in cellular and organoid models.

Conclusions:

• Enhancing SNCA-LC3 interactions can promote SNCA autophagic degradation.
• R406 represents a potential therapeutic agent for Parkinson disease by lowering SNCA levels.
• Targeting SNCA autophagic degradation offers a promising avenue for PD treatment.