The integrated stress response in Vanishing White Matter: insight into disease mechanisms and therapy targets

Vanishing white matter (VWM) is a devastating brain white matter disorder. Patients experience chronic progressive neurological deterioration with episodes of rapid decline induced by specific stressors This condition results in premature death, and there is currently no curative treatment available. Ataxia is a prominent clinical feature, alongside cognitive impairments. On a pathological level, VWM is marked by rarefaction of white matter, deficiencies in myelin, and abnormal development of brain cells such as astrocytes and oligodendrocytes. VWM is caused by bi-allelic pathogenic mutations in any of the five genes encoding subunits (α-ε) of eukaryotic initiation factor 2B (eIF2B), a protein essential for initiating mRNA translation and regulating protein synthesis. eIF2B also plays a central role in the integrated stress response (ISR), a cellular mechanism activated by various types of stress. In response to stress, eIF2α becomes phosphorylated (p-eIF2α), inhibitng eIF2B, thereby reducing general protein synthesis and promoting the production of stress-related transcription factors such as ATF4 and CHOP. These factors regulate the expression of genes that help cells cope with stress. VWM variants result in reduced eIF2B activity and dysregulation of the ISR. This leads to sustained activation of ATF4 and CHOP, despite low levels of p-eIF2α, contributing to disease progression. The degree of ISR dysregulation correlates with the severity of the disease. eIF2B has emerged as a potential therapy target, and stimulating its activity could offer therapeutic benefits. The aim of this thesis was to increase mechanistic insight into the dysregulated ISR in VWM and to identify new therapeutic targets. Key findings include: 1. Lithium: Initially thought to improve eIF2B activity by inhibiting GSK3β, lithium showed limited efficacy and significant side effects, making it unsuitable for VWM treatment. 2. TUDCA and 4-PBA: These compounds reduce p-eIF2α levels but showed minimal effects in VWM models, reinforcing that targeting downstream of eIF2B is more effective. 3. Pridopidine (PDPD): Acting downstream of eIF2B, PDPD mildly improved motor symptoms in VWM mice but was not effective enough for standalone therapy. 4. Guanabenz (GBZ) and Sephin1 (S1): GBZ significantly reduced ISR activation and improved symptoms in VWM mice, while Sephin1, lacking adrenergic effects, was less effective. 5. CHOP: Deleting CHOP significantly alleviated disease symptoms, confirming its central role in disease severity. However, other ISR components like ATF4 and GADD34 remained active. 6. ATF4 and GADD34: Reducing ATF4 and deleting GADD34 improved symptoms, indicating their significant role in disease progression. Guanabenz and dexmedetomidine, by activating α2-adrenergic receptors, also reduced ISR markers, further supporting their therapeutic potential. At the conclusion of this research, GBZ and eIF2B activators are being investigated as potential therapies for VWM. The studies highlighted that targeting ISR components at or downstream of eIF2B is more effective than upstream approaches. Importantly, a distinction was made between ATF4 and ATF4 & CHOP co-regulated branches of the ISR in relation to disease severity, providing insights into how brain pathology relates to disease progression in VWM mice.