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Article

Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both Mutant ATXN3 and LC3

by
Te-Hsien Lin
1,†,
Wan-Ling Chen
1,†,
Shao-Fan Hsu
2,
I-Cheng Chen
2,
Chih-Hsin Lin
1,
Kuo-Hsuan Chang
1,
Yih-Ru Wu
1,
Yi-Ru Chen
3,
Ching-Fa Yao
3,
Wenwei Lin
3,
Guey-Jen Lee-Chen
2,* and
Chiung-Mei Chen
1,*
1
Department of Neurology, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Taoyuan 33302, Taiwan
2
Department of Life Science, National Taiwan Normal University, Taipei 11677, Taiwan
3
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2024, 25(19), 10707; https://doi.org/10.3390/ijms251910707
Submission received: 10 September 2024 / Revised: 1 October 2024 / Accepted: 2 October 2024 / Published: 4 October 2024
(This article belongs to the Special Issue Molecular Mechanisms of Neurological and Psychiatric Disease: A Decade of Progress)
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Abstract

Polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA), including SCA1, 2, 3, 6, 7, and 17, are caused by mutant genes with expanded CAG repeats, leading to the intracellular accumulation of aggregated proteins, the production of reactive oxygen species, and cell death. Among SCA, SCA3 is caused by a mutation in the ATXN3 (ataxin-3) gene. In a circumstance of polyQ aggregation, the autophagic pathway is induced to degrade the aggregated proteins, thereby suppressing downstream deleterious effects and promoting neuronal survival. In this study, we tested the effects of synthetic indole (NC009-1, -2, -3, -6) and coumarin (LM-022, -031) derivatives as chemical chaperones to assist mutant ATXN3-Q75 folding, as well as autophagy inducers to clear aggregated protein. Among the tested compounds, NC009-1, -2, and -6 and LM-031 interfered with Escherichia coli-derived ATXN3-Q75 aggregation in thioflavin T binding and filter trap assays. In SH-SY5Y cells expressing GFP-fused ATXN3-Q75, these compounds displayed aggregation-inhibitory and neurite growth-promoting potentials compared to untreated cells. Furthermore, these compounds activated autophagy by increasing the phosphatidylethanolamine-conjugated LC3 (microtubule associated protein 1 light chain 3)-II:cytosolic LC3-I ratio in these cells. A biochemical co-immunoprecipitation assay by using a mixture of HEK 293T cell lysates containing recombinant ATXN3-Q75-Venus-C-terminus (VC) or Venus-N-terminus (VN)-LC3 protein indicated that NC009-1 and -2 and LM-031 served as an autophagosome-tethering compound (ATTEC) to interact with ATXN3-Q75 and LC3, and the interaction was further confirmed by bimolecular fluorescence complementation analysis in cells co-expressing both ATXN3-Q75-VC and VN-LC3 proteins. The study results suggest the potential of NC009-1 and -2 and LM-031 as an ATTEC in treating SCA3 and, probably, other polyQ diseases.
Keywords: ATXN3; autophagosome tethering; LC3; polyglutamine; SCA3 therapeutics; venus-based BiFC ATXN3; autophagosome tethering; LC3; polyglutamine; SCA3 therapeutics; venus-based BiFC

Share and Cite

MDPI and ACS Style

Lin, T.-H.; Chen, W.-L.; Hsu, S.-F.; Chen, I.-C.; Lin, C.-H.; Chang, K.-H.; Wu, Y.-R.; Chen, Y.-R.; Yao, C.-F.; Lin, W.; et al. Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both Mutant ATXN3 and LC3. Int. J. Mol. Sci. 2024, 25, 10707. https://doi.org/10.3390/ijms251910707

AMA Style

Lin T-H, Chen W-L, Hsu S-F, Chen I-C, Lin C-H, Chang K-H, Wu Y-R, Chen Y-R, Yao C-F, Lin W, et al. Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both Mutant ATXN3 and LC3. International Journal of Molecular Sciences. 2024; 25(19):10707. https://doi.org/10.3390/ijms251910707

Chicago/Turabian Style

Lin, Te-Hsien, Wan-Ling Chen, Shao-Fan Hsu, I-Cheng Chen, Chih-Hsin Lin, Kuo-Hsuan Chang, Yih-Ru Wu, Yi-Ru Chen, Ching-Fa Yao, Wenwei Lin, and et al. 2024. "Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both Mutant ATXN3 and LC3" International Journal of Molecular Sciences 25, no. 19: 10707. https://doi.org/10.3390/ijms251910707

APA Style

Lin, T.-H., Chen, W.-L., Hsu, S.-F., Chen, I.-C., Lin, C.-H., Chang, K.-H., Wu, Y.-R., Chen, Y.-R., Yao, C.-F., Lin, W., Lee-Chen, G.-J., & Chen, C.-M. (2024). Small Molecules Inducing Autophagic Degradation of Expanded Polyglutamine Protein through Interaction with Both Mutant ATXN3 and LC3. International Journal of Molecular Sciences, 25(19), 10707. https://doi.org/10.3390/ijms251910707

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