Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1

Yang, Chen; Gravendeel, Nienke; On, Amy Chin; Post, Laura; van Bergen, Ryan; Osorio, Catarina; Schonewille, Martijn

doi:10.3390/ijms26104698

Open AccessArticle

Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1

by

Chen Yang

,

Nienke Gravendeel

,

Amy Chin On

,

Laura Post

,

Ryan van Bergen

,

Catarina Osorio

and

Martijn Schonewille

^*

Department of Neuroscience, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(10), 4698; https://doi.org/10.3390/ijms26104698

Submission received: 12 March 2025 / Revised: 5 May 2025 / Accepted: 8 May 2025 / Published: 14 May 2025

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

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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder that predominantly affects the Purkinje cells (PCs) of the cerebellum, leading to cerebellar degeneration, motor dysfunction, and cognitive impairment. Sphingosine-1-phosphate (S1P) signaling, known to modulate neuroinflammation, has been identified as a potential therapeutic target in SCA1. To investigate the therapeutic efficacy of the S1P modulator fingolimod, we treated a mouse model for SCA1, ATXN1[82Q]/+ mice during three different periods with fingolimod and assessed the effects. Potential therapeutic effects were monitored by tracking locomotion during the treatment period and examining PC morphology, connectivity, and markers for neuroinflammation post-mortem. Fingolimod treatment reduced astrocyte and microglial activation during all three treatment periods. We found no effect on calbindin levels or the thickness of the molecular layer, but fingolimod did improve the extent of the synaptic input of climbing fibers to PCs. While fingolimod improved important aspects of cellular pathology, we could only detect signs of improvement in the locomotion phenotype when treatment started at a later stage of the disease. In conclusion, fingolimod is able to mitigate neuroinflammation, preserve aspects of PC function in SCA1, and remediate part of the ataxia phenotype when treatment is appropriately timed. Although behavioral benefits were limited, targeting S1P pathways represents a potential therapeutic strategy for SCA1. Further studies are needed to optimize treatment regimens and assess long-term outcomes.

Keywords: spinocerebellar ataxia type 1; neuroinflammation; fingolimod; microglia; sphingosine-1-phosphate pathway

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MDPI and ACS Style

Yang, C.; Gravendeel, N.; On, A.C.; Post, L.; van Bergen, R.; Osorio, C.; Schonewille, M. Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1. Int. J. Mol. Sci. 2025, 26, 4698. https://doi.org/10.3390/ijms26104698

AMA Style

Yang C, Gravendeel N, On AC, Post L, van Bergen R, Osorio C, Schonewille M. Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1. International Journal of Molecular Sciences. 2025; 26(10):4698. https://doi.org/10.3390/ijms26104698

Chicago/Turabian Style

Yang, Chen, Nienke Gravendeel, Amy Chin On, Laura Post, Ryan van Bergen, Catarina Osorio, and Martijn Schonewille. 2025. "Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1" International Journal of Molecular Sciences 26, no. 10: 4698. https://doi.org/10.3390/ijms26104698

APA Style

Yang, C., Gravendeel, N., On, A. C., Post, L., van Bergen, R., Osorio, C., & Schonewille, M. (2025). Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1. International Journal of Molecular Sciences, 26(10), 4698. https://doi.org/10.3390/ijms26104698

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Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1

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