Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1

Burján, Tímea; Aslam, Maryam; Keresztes, Fanni; Sigmond, Tímea; Billes, Viktor A.; Bencsik, Norbert; Schlett, Katalin; Vellai, Tibor; Kovács, Tibor

doi:10.3390/ijms262110443

This is an early access version, the complete PDF, HTML, and XML versions will be available soon.

Open AccessArticle

Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1

by

Tímea Burján

^1,2,†,

Maryam Aslam

^1,2,†,

Fanni Keresztes

^1,2,

Tímea Sigmond

¹

,

Viktor A. Billes

¹,

Norbert Bencsik

³

,

Katalin Schlett

³

,

Tibor Vellai

^1,4,* and

Tibor Kovács

^1,*

¹

Department of Genetics, Eötvös Loránd University (ELTE), 1053 Budapest, Hungary

²

Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Pázmány Péter sétány 1/C, 1053 Budapest, Hungary

³

Department of Physiology and Neurobiology, Eötvös Loránd University (ELTE), 1053 Budapest, Hungary

⁴

HUNREN-ELTE Genetic Research Group, 1097 Budapest, Hungary

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(21), 10443; https://doi.org/10.3390/ijms262110443

Submission received: 23 September 2025 / Revised: 22 October 2025 / Accepted: 24 October 2025 / Published: 27 October 2025

(This article belongs to the Special Issue New Mechanisms and Therapeutics in Neurological Diseases—4th Edition)

Download Versions Notes

Abstract

Autophagy is a lysosome-mediated self-degradation process of eukaryotic cells which is critical for the elimination of cellular damage. Its capacity progressively declines with age, and this change can lead to the development of various neurodegenerative pathologies including Spinocerebellar ataxia type 1 (SCA1). SCA1 is mainly caused by mutations in the polyglutamine region of Ataxin 1 protein. In patients affected by the disease, Purkinje neurons of the cerebellum frequently undergo demise and eventually become lost. Here we tested whether two well-characterized autophagy-enhancing small molecules, AUTEN-67 and -99, which antagonize the autophagy complex Vps34 through blocking the myotubularin-related lipid phosphatase MTMR14/EDTP, have the capacity to ameliorate SCA1 symptoms. We found that in a Drosophila model of SCA1, only AUTEN-67 exerts positive effects including improvement in climbing ability and extending life span. Based on these results, we hypothesized that the two compounds influence autophagy in the brain in a neuron-specific manner. Indeed, according to data we obtained, AUTEN-67 and -99 exhibit shared and unique functional domains in the Drosophila brain. AUTENs enhance autophagy in GABAergic and dopaminergic neurons. In addition, AUTEN-67 also affect autophagy in cholinergic neurons, while AUTEN-99 trigger the process in glutaminergic neurons and motoneurons. We also observed varying efficiencies between the two AUTENs among different subtypes of cultured hippocampal neurons of mice. These data suggest that the two compounds display neuron-specific differences in exerting autophagy-enhancing effects, and may lead to a better understanding of which types of neurons autophagy could potentially be activated to treat SCA1 in human patients.

Keywords: aging 1; AUTEN-67 2; AUTEN-99 3; autophagy 4; Drosophila 5; EDTP 6; MTMR14 7; neurodegeneration 8; SCA1 9

Share and Cite

MDPI and ACS Style

Burján, T.; Aslam, M.; Keresztes, F.; Sigmond, T.; Billes, V.A.; Bencsik, N.; Schlett, K.; Vellai, T.; Kovács, T. Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1. Int. J. Mol. Sci. 2025, 26, 10443. https://doi.org/10.3390/ijms262110443

AMA Style

Burján T, Aslam M, Keresztes F, Sigmond T, Billes VA, Bencsik N, Schlett K, Vellai T, Kovács T. Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1. International Journal of Molecular Sciences. 2025; 26(21):10443. https://doi.org/10.3390/ijms262110443

Chicago/Turabian Style

Burján, Tímea, Maryam Aslam, Fanni Keresztes, Tímea Sigmond, Viktor A. Billes, Norbert Bencsik, Katalin Schlett, Tibor Vellai, and Tibor Kovács. 2025. "Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1" International Journal of Molecular Sciences 26, no. 21: 10443. https://doi.org/10.3390/ijms262110443

APA Style

Burján, T., Aslam, M., Keresztes, F., Sigmond, T., Billes, V. A., Bencsik, N., Schlett, K., Vellai, T., & Kovács, T. (2025). Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1. International Journal of Molecular Sciences, 26(21), 10443. https://doi.org/10.3390/ijms262110443

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Comparative Analysis of Two Autophagy-Enhancing Small Molecules (AUTEN-67 and -99) in a Drosophila Model of Spinocerebellar Ataxia Type 1

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI