Scientists at the University of Buffalo have identified a critical step in the process of nerve myelination after birth, a discovery that holds promise for the development of more effective therapies for neurodegenerative diseases like multiple sclerosis (MS). The research involved the study of voltage-operated calcium channels, which initiate many physiological functions.
The UB investigative team published a research article in the Journal of Neuroscience describing preclinical research concerning the oligodendrocyte cells that create myelin — the protective coating that neurons need to function — and progenitor cells that are their precursors.
The paper, “Conditional Deletion of the L-Type Calcium Channel Cav1.2 in Oligodendrocyte Progenitor Cells Affects Postnatal Myelination in Mice,” explains how myelin is lost or damaged in MS and similar diseases.
“If we can further enhance our understanding of how these oligodendrocyte precursor cells mature, then it may be possible to stimulate them to replace myelin in diseases like multiple sclerosis,” said Pablo M. Paez, PhD, a member of the research team and paper co-author, in a press release.
“Our findings show that these calcium channels modulate the maturation of oligodendrocytes in the brain after birth. That’s important because it’s possible that the activity of this calcium channel can be manipulated pharmacologically to encourage oligodendrocyte maturation and remyelination after demyelinating episodes in the brain,” he said.
The investigative team found that within two weeks after birth, oligodendrocyte maturation and myelination are able to proceed, provided calcium channels are functioning properly.
In experiments with mice from which these calcium channels had been removed, abnormal oligodendrocyte maturation prevented normal myelination. Reduced myelination was accompanied by a significant decline in the number of myelinating oligodendrocytes and in the rate of oligodendrocyte progenitor cell proliferation.
The authors report that it is clear that cells in the oligodendrocyte lineage exhibit remarkable plasticity with regard to the expression of calcium channels and that disturbing calcium homeostasis (equilibrium) likely plays an important role in demyelinating disease development.
Their results indicate that voltage-operated calcium channels can modulate oligodendrocyte development in the postnatal brain, suggesting that voltage-gated calcium influx in oligodendroglial cells is critical to the process of normal myelination — findings they say could lead to novel approaches to to treating neurodegenerative diseases involving myelin loss or damage.
Paez said it appears that in animal models, the inability to develop myelin normally persists into adulthood, which he says suggests that expression of voltage-operated calcium channels during the first myelination phases is essential for normal brain development.
“Demyelination — the loss of myelin — impairs the ability of nerve impulses to travel from nerve cell to nerve cell,” Paez said. “That can lead to deficits in motor, sensory and cognitive function. While remyelination occurs in many multiple sclerosis lesions, this becomes increasingly less effective over time and eventually fails.”
Paez says these research results are of particular interest because many therapies that target calcium channels are already on the market for treating cardiovascular disorders and other diseases.
“The pharmacology of these calcium channel blockers is very well-understood, so an understanding of how they influence myelination could potentially bring us closer to new therapies more rapidly than some other therapeutic possibilities,” said Lawrence Wrabetz, MD, a professor of neurology and biochemistry, and director of the Hunter James Kelly Research Institute (HJKRI), part of UB’s New York State Center of Excellence in Bioinformatics and Life Sciences.
Scientists at The Wrabetz Laboratory at HJKRI are particularly interested in the molecular genetics of myelination, which they study primarily in transgenic mice. Their research concentrates on the development of inherited demyelinating diseases and the development and characterization of mouse models of Charcot-Marie-Tooth (CMT) neuropathies.
Most of the research work was conducted at HJKRI, and the study was supported by the National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society.
Paez’s co-authors from HJKRI are Veronica T. Cheli, Diara A. Santiago Gonzalez, Tenzing Namgyal Lama, and Vilma Spreuer. Researchers from the David Geffen School of Medicine at UCLA and the University of Michigan were also co-authors.