Pelizaeus-Merzbacher disease (PMD) is a recessive x-linked genetic disorder that typically causes leukodystrophy of male’s central nervous system (brain and spinal cord). Leukodystrophy is a result of mutations in the PLP1 gene [3]. These mutations include gene duplication, missense, frameshift, and deletion. Leukodystrophy is when the myelin sheath fails to form. The myelin sheath is extremely important in axon insulation and rapid transmission of action potentials. It’s produced by oligodendrocytes which consistently die due to cellular stress in patients with PMD. Without the insulation of the myelin sheath, impulses become weak and/or fail to deliver. This can cause symptoms that include weak muscles, cognitive delays, and respiratory issues. Severe cases can lead to death early on in life and there is currently no way of curing this disease. Patients are given symptom management options that may slightly improve their quality of life but this does not extend their lifespan.
In a research presentation given by Dr. Yanan Chen, Chen addressed the lack of treatment options for patients with PMD and is working to contribute to finding a cure. By using a Jimpy mouse model that replicated PMD resulting from frameshift mutations in the PLP1 gene, she was able to discover how inhibiting the integrated stress response (ISR) decreases oligodendrocyte death [1]. The ISR is an important pathway that allows cells to combat stress. This stress may be caused by things such as protein misfolding, which is a result of frameshift mutations in the PLP1 gene. Her discovery highlighted a potential method that could be used to better treat patients with PMD; however Chen does not experiment using models where PMD is a result of other mutations. She addressed the different mutations that cause PMD but does no further research on it.
In a similar research study done by Zachary Nevin et al., Nevin investigated the role that the different mutations have on the development of PMD. This study used a human induced pluripotent stem cell (hiPSC) that they generated from 12 people with different PLP1 gene mutations [2]. Although they were able to find shared defects caused by each individual mutation, there were also many differences, especially in oligodendrocyte development and ability to form the myelin sheath, which was studied heavily in Yanan Chen’s lab. Nevin et al.’s research suggests that different PLP1 gene mutations may require different treatments. His discovery indicates that it would be difficult to have one specific treatment for a group of PMD patients with different PLP1 gene mutations.
Dr. Zachary Nevin’s work reveals that Dr. Yanan Chen’s method of inhibiting the ISR may only work for certain mutations. Although more research needs to be done to develop a way to treat PMD, both studies have brought us closer to developing a viable treatment for PMD. Patients are closer to the opportunity of a longer and healthy lifespan.
References:
1. Chen, Y., & et. al. (n.d.). Integrated stress response inhibition prolongs the lifespan of a pelizaeus-merzbacher disease mouse model by increasing oligodendrocyte survival. Nature communications. https://pubmed.ncbi.nlm.nih.gov/41453885/
2. Nevin , Z., & et al. (n.d.). Modeling the mutational and phenotypic landscapes of Pelizaeus-Merzbacher disease with human IPSC-derived oligodendrocytes. American journal of human genetics. https://pubmed.ncbi.nlm.nih.gov/28366443/
3. U.S. National Library of Medicine. (n.d.). Pelizaeus-Merzbacher Disease: Medlineplus genetics. MedlinePlus. https://medlineplus.gov/genetics/condition/pelizaeus-merzbacher-disease/
No comments:
Post a Comment