Trehalose consumption ameliorates pathogenesis in an inducible mouse model of the Fragile X-associated tremor/ataxia syndrome

ABSTRACT

Trehalose is a naturally occurring sugar found in various food and pharmaceutical preparations with the ability to enhance cellular proteostasis and reduce the formation of toxic intracellular protein aggregates, making it a promising therapeutic candidate for various neurodegenerative disorders.

Objectives

Here, we explored the effectiveness of nutritional trehalose supplementation in ameliorating symptoms in a mouse model of Fragile X-associated tremor/ataxia syndrome (FXTAS), an incurable late onset manifestation of moderately expanded trinucleotide CGG repeat expansion mutations in the 5’ untranslated region of the fragile X messenger ribonucleoprotein 1 gene (FMR1).

Methods

An inducible mouse model of FXTAS expressing 90 CGG repeats in the brain had been previously developed, which faithfully captures hallmarks of the disorder, the formation of intracellular inclusions, and the disturbance of motor function. Taking advantage of the inducible nature of the model, we investigated the therapeutic potential of orally administered trehalose under two regimens, modelling disease prevention and disease treatment.

Results and Discussion

Trehalose's effectiveness in combating protein aggregation is frequently attributed to its ability to induce autophagy. Accordingly, trehalose supplementation under the prevention regimen ameliorated the formation of intranuclear inclusions and improved the motor deficiencies resulting from the induced expression of 90 CGG repeats, but it failed to reverse the existing nuclear pathology as a treatment strategy. Given the favorable safety profile of trehalose, it is promising to further explore the potential of this agent for early stage FXTAS.

KEYWORDS:

• FXTAS
• repeat expansion
• neurodegeneration
• cerebellum
• motor behavior
• trehalose
• autophagy
• transgenic mouse

Acknowledgements

We are grateful to F. Blitz, A. Koffi von Hoff, and S. Stork for expert technical assistance and A. Bohnstedt and D. Al-Chakmakchi for devoted and impeccable animal care.

Disclosure statement

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

Disclosure of interest

The authors report there are no competing interests to declare.

Data availability statement

The data that support the findings of this study are available from the corresponding author, O.S., upon reasonable request.

Additional information

Funding

This work was supported by the Deutsche Forschungsgemeinschaft under grant 3038041027; STO488/9-1 (RU5228 Syntophagy) and 362321501 (RTG 2413 SynAGE) and by the E-Rare under 01GM1505 ERARE; DrugFXSPreMut to O.S.

Notes on contributors

Emre Kul

Emre Kul is a neurobiologist with a background in chemistry. He obtained his Ph.D. degree from the Otto-von-Guericke-University Magdeburg, Germany, where he conducted research on mouse models of cerebellar neurodegeneration. His work focused on developing therapeutic strategies for Fragile X-associated tremor/ataxia syndrome (FXTAS), including the use of antisense oligonucleotide therapy and other FDA-approved compounds. Currently, Emre is dedicated to developing novel, high-capacity gene delivery vectors and investigates their applications in gene therapy approaches for monogenic cerebellar ataxias.

Oliver Stork

Oliver Stork is a neurobiologist with a background in behavioural and molecular neurobiology. He obtained his Ph.D. from the Swiss Federal Technical University Zürich in 1997 and is Professor for Molecular Neurobiology at the Otto-von-Guericke-University Magdeburg since 2008. His research is devoted to the understanding of molecular mechanisms that underlie information storage in the central nervous system and the control of behaviour. In particular, he focusses on the processes in brain circuits that mediate the translation of specific neuronal activity patterns into lasting morphological and neurochemical changes and their relevance for learning and memory, stress, and ageing.