Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter

Ellen Oudejans, Diede Witkamp, Gino V. Hu-A-ng, Leoni Hoogterp, Gemma van Rooijen-van Leeuwen, Iris Kruijff, Pleun Schonewille, Zeinab Lalaoui El Mouttalibi, Imke Bartelink, Marjo S. van der Knaap, Truus E. M. Abbink

Research output: Contribution to journalArticleAcademicpeer-review


The leukodystrophy vanishing white matter (VWM) is characterized by chronic and episodic acute neurological deterioration. Curative treatment is presently unavailable. Pathogenic variants in the genes encoding eukaryotic initiation factor 2B (eIF2B) cause VWM and deregulate the integrated stress response (ISR). Previous studies in VWM mouse models showed that several ISR-targeting compounds ameliorate clinical and neuropathological disease hallmarks. It is unclear which ISR components are suitable therapeutic targets. In this study, effects of 4-phenylbutyric acid, tauroursodeoxycholic acid, or pridopidine (PDPD), with ISR targets upstream or downstream of eIF2B, were assessed in VWM mice. In addition, it was found that the composite ataxia score represented motor decline of VWM mice more accurately than the previously used neuroscore. 4-phenylbutyric acid and tauroursodeoxycholic acid did not improve VWM disease hallmarks, whereas PDPD had subtle beneficial effects on motor skills. PDPD alone does not suffice as treatment in VWM mice but may be considered for combination therapy. Also, treatments aimed at ISR components upstream of eIF2B do not improve chronic neurological deterio-ration; effects on acute episodic decline remain to be investigated.
Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalLife Science Alliance
Issue number3
Early online date3 Jan 2024
Publication statusPublished - 1 Mar 2024

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