Abstract
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 language | English |
|---|---|
| Pages (from-to) | 1-10 |
| Number of pages | 10 |
| Journal | Life science alliance |
| Volume | 7 |
| Issue number | 3 |
| Early online date | 3 Jan 2024 |
| DOIs | |
| Publication status | Published - Mar 2024 |
Bibliographical note
Funding Information:We thank Janneke Witvliet and Milo Zˇnidarsˇicˇ for technical assistance with the in vivo experiments. We thank Javier Triñanes Ramos for imaging the thioflavin T–stained sections. We thank Dr. Tanzeer Kaur (Panjab University, Chandigarh) for providing a protocol for 4-PBA preparation. We thank Pri-lenia for providing the pridopidine. We thank the animal caretakers of the VU-VUmc animal facility for mouse breeding and advice. This study was supported by ELA grant 2020-02712 and ZonMW TOP grant 91217006.
Funding Information:
We thank Janneke Witvliet and Milo Žnidaršič for technical assistance with the in vivo experiments. We thank Javier Triñanes Ramos for imaging the thioflavin T–stained sections. We thank Dr. Tanzeer Kaur (Panjab University, Chandigarh) for providing a protocol for 4-PBA preparation. We thank Prilenia for providing the pridopidine. We thank the animal caretakers of the VU-VUmc animal facility for mouse breeding and advice. This study was supported by ELA grant 2020-02712 and ZonMW TOP grant 91217006.
Publisher Copyright:
© 2024 Oudejans et al.
Funding
We thank Janneke Witvliet and Milo Zˇnidarsˇicˇ for technical assistance with the in vivo experiments. We thank Javier Triñanes Ramos for imaging the thioflavin T–stained sections. We thank Dr. Tanzeer Kaur (Panjab University, Chandigarh) for providing a protocol for 4-PBA preparation. We thank Pri-lenia for providing the pridopidine. We thank the animal caretakers of the VU-VUmc animal facility for mouse breeding and advice. This study was supported by ELA grant 2020-02712 and ZonMW TOP grant 91217006. We thank Janneke Witvliet and Milo Žnidaršič for technical assistance with the in vivo experiments. We thank Javier Triñanes Ramos for imaging the thioflavin T–stained sections. We thank Dr. Tanzeer Kaur (Panjab University, Chandigarh) for providing a protocol for 4-PBA preparation. We thank Prilenia for providing the pridopidine. We thank the animal caretakers of the VU-VUmc animal facility for mouse breeding and advice. This study was supported by ELA grant 2020-02712 and ZonMW TOP grant 91217006.
| Funders | Funder number |
|---|---|
| ZonMw TOP | 91217006 |
| Chandigarh University | |
| Association Européenne contre les Leucodystrophies | 2020-02712 |
| Association Européenne contre les Leucodystrophies |