Related Experiment Video

Updated: Jun 10, 2025

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

592

Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both

Te-Hsien Lin1, Wan-Ling Chen1, Shao-Fan Hsu2

  • 1Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, Taiwan.

International Journal of Molecular Sciences
|October 16, 2024
PubMed

Insights

New compounds NC009-1, -2, -6 and LM-031 inhibit polyglutamine aggregation and promote neuronal survival in spinocerebellar ataxia models. These compounds act as autophagosome-tethering compounds (ATTECs), enhancing the clearance of toxic proteins.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Polyglutamine (polyQ) diseases, including spinocerebellar ataxia (SCA), result from expanded CAG repeats in specific genes.
  • SCA type 3 (SCA3) is caused by mutations in the ATXN3 gene, leading to toxic protein aggregation and neuronal death.
  • Autophagy is a cellular process that degrades aggregated proteins, offering a potential therapeutic target for polyQ diseases.

Purpose of the Study:

  • To evaluate synthetic indole and coumarin derivatives as chemical chaperones and autophagy inducers for treating SCA3.
  • To investigate the compounds' ability to inhibit mutant ATXN3 aggregation and promote neuronal survival.
  • To determine if these compounds can act as autophagosome-tethering compounds (ATTECs) to facilitate protein clearance.

Main Methods:

  • In vitro aggregation assays using purified ATXN3-Q75 and thioflavin T binding.
  • Cellular assays in SH-SY5Y cells expressing ATXN3-Q75 to assess aggregation inhibition and neurite outgrowth.
  • Biochemical assays, including co-immunoprecipitation and bimolecular fluorescence complementation, to confirm ATTEC activity.

Main Results:

  • Compounds NC009-1, -2, -6, and LM-031 inhibited ATXN3-Q75 aggregation in vitro.
  • These compounds reduced ATXN3-Q75 aggregation and promoted neurite growth in neuronal cells.
  • NC009-1, -2, and LM-031 were identified as ATTECs, bridging mutant ATXN3 and LC3 for autophagosomal degradation.

Conclusions:

  • Selected indole and coumarin derivatives demonstrate efficacy in reducing polyQ aggregation and enhancing neuronal health.
  • NC009-1, -2, and LM-031 function as ATTECs, representing a novel therapeutic strategy for SCA3.
  • These compounds hold promise for treating SCA3 and potentially other polyglutamine-related neurodegenerative diseases.
Keywords:
ATXN3LC3SCA3 therapeuticsautophagosome tetheringpolyglutaminevenus-based BiFC

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