A Northwestern Medicine study has uncovered a promising new therapeutic approach for a rare genetic brain disorder, according to findings published in Nature Communications.
Pelizaeus-Merzbacher disease (PMD), a rare genetic disorder that disrupts brain myelination and leads to severe neurological impairment, is caused by mutations in the PLP1 gene, which results in the death of oligodendrocytes — cells responsible for producing myelin, the protective sheath around nerve fibers.
In its most severe forms, PMD disrupts normal development and is usually fatal in early childhood. Currently, there is no cure, and treatment consists of managing symptoms.
“PMD is a severe genetic neurological disorder that is X-linked, such that it primarily affects males,” said Brian Popko, PhD, the William Frederick Windle Professor of Neurology and senior author of the study. “PMD is referred to as a leukodystrophy because it results in abnormalities in the white matter, or myelin, of the brain and spinal cord. When this insulation is missing or damaged, the brain cannot send clear signals to the rest of the body.”
To better understand disease progression and explore potential therapies, scientists in the Popko laboratory studied a mouse model of PMD. The team focused on the integrated stress response (ISR), a cellular defense mechanism activated by the mutant PLP protein.
“The ISR provides transient protection to cells to various stresses, but we speculated that its constant activation due to the continuous production of mutant PLP, could be detrimental to the affected cells,” said Popko, who is also Scientific Director of MS and Neuroimmunology within The Ken & Ruth Davee Department of Neurology’s Division of Multiple Sclerosis and Neuroimmunology.
They found that disabling PERK, a key ISR-triggering enzyme, significantly extended the lifespan of the mice by improving oligodendrocyte survival and boosting myelination. Promisingly, the team also observed that 2BAct, a small-molecule ISR inhibitor, provided similar benefits in mice.
These results suggest that targeting ISR pathways could be a promising treatment direction for PMD, Popko said.
Looking ahead, the team plans to explore whether this approach works across different PMD-causing mutations. Additionally, Popko and his collaborators hope to further test ISR inhibitors in PMD.
“Because this type of treatment is already making its way through the regulatory process, our findings in the lab could be fast-tracked toward a human therapy for PMD,” Popko said.
The study was supported by National Institutes of Health grants 5R01NS034939 and 1R35NS137478, as well as the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Rampy MS Research Foundation.
