Glutamine stimulates the S6K/4E-BP branch of insulin signalling pathway to mitigate human poly(Q) disorders in Drosophila disease models

ABSTRACT

Human polyglutamine [poly(Q)] disorders such as Huntington's disease, different types of ataxias, etc. are devastating brain illnesses which are characterised by the presence of neurotoxic protein aggregates in the affected neurons. We have recently reported that S6K/4E-BP mediated growth promoting branch of insulin signalling pathway alleviates human poly(Q) induced neurotoxicity in Drosophila disease models.

Objective and Methods

Since, the S6K/4E-BP sub-pathway can be stimulated by various amino acids; we extended our investigation to examine if oral feeding of amino acids delivers rescue against human poly(Q) toxicity in Drosophila. We utilised Drosophila models of two different poly(Q) disorders to test our hypothesis. Glutamine was fed to the test flies orally mixed in the food. Control and treated flies were then tested for different parameters, such as formation of poly(Q) aggregates and neurodegeneration, to evaluate glutamine’s proficiency in mitigating poly(Q) neurotoxicity.

Results

Our study, for the first time, reports that glutamine feeding stimulates the growth promoting S6K/4E-BP branch of insulin signalling pathway and restricts pathogenesis of poly(Q) disorders in Drosophila disease models. We noted that glutamine treatment restricts the formation of neurotoxic poly(Q) aggregates and minimises neuronal deaths. Further, glutamine treatment re-establishes the chromatin architecture by improving the histone acetylation which is otherwise compromised in poly(Q) expressing neuronal cells.

Discussion

Since, the insulin signalling pathway as well as mechanism of action of glutamine are fairly conserved between human and Drosophila, our finding strongly suggests that glutamine holds immense potential to be developed as an intervention therapy against the incurable human poly(Q) disorders.

KEYWORDS:

• Poly(Q) disorders
• Huntington's disease
• SCA3‌
• neurodegeneration
• glutamine
• insulin pathway
• Drosophila
• S6K/4E-BP

Acknowledgements

We thank Prof. Troy Littleton, MIT, USA, and Bloomington Stock Center, USA, for fly stocks. We also thank Delhi University for support under Faculty Research Program (FRP) of the IoE scheme, and the Central Instrument Facility (CIF) at South Campus. We are grateful to Ms. Nabanita Sarkar for technical support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Surajit Sarkar and Shweta Tandon conceived the project. Shweta Tandon performed the experiments. Shweta Tandon and Surajit Sarkar analysed the data. Shweta Tandon and Surajit Sarkar wrote the manuscript. Funding acquisition: Surajit Sarkar.

Ethics approval statement

Ethical approval is not required for this study.

Data availability statement

All the data that support the findings have been provided with the manuscript. Any additional information, raw images, analysis data are available from the corresponding author, upon reasonable request.

Additional information

Funding

This work was supported by Department of Biotechnology, Government of India, New Delhi [grant number BT/PR15492/MED/122/46/2016]; University Grants Commission [grant number 20/12/2015(ii)EU-V].

Notes on contributors

Shweta Tandon

Shweta Tandon Neurobiologist. Master's degree from Himachal Pradesh University, Shimla, India. PhD in Genetics from the University of Delhi (South Campus), New Delhi, India. Her research focuses on investigating the precise involvement of insulin signalling pathway in pathogenesis of human poly(Q) disorders, and screening/characterisation of compatible genetic modifiers and drug molecules.

Surajit Sarkar

Surajit Sarkar Neurobiologist. Professor of Genetics at the University of Delhi (South Campus), New Delhi, India. PhD in Zoology from Banaras Hindu University, India; worked as a visiting associate at California Institute of Technology, Pasadena, USA. Research work consists in investigating the cellular and molecular in-depths of human neurodegenerative disorders with identification and characterisation druggable genetic modifiers and drug molecules using Drosophila disease models.