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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 deterioration; effects on acute episodic decline remain to be investigated.<\/jats:p>","DOI":"10.26508\/lsa.202302199","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T23:38:24Z","timestamp":1704325104000},"page":"e202302199","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Pridopidine subtly ameliorates motor skills in a mouse model for vanishing white matter"],"prefix":"10.26508","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-490X","authenticated-orcid":true,"given":"Ellen","family":"Oudejans","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05grdyy37","id-type":"ROR","asserted-by":"publisher"}],"name":"Child Neurology, Emma Children\u2019s Hospital, Amsterdam Leukodystrophy Center, Amsterdam University Medical Centers","place":[", Vrije 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