Research Paper Volume 8, Issue 11 pp 2667—2688
The progeroid gene BubR1 regulates axon myelination and motor function
- 1 Department of Neurologic Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- 2 Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- 3 Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- 4 Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
- 5 Departments of Neurology and Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
Received: May 12, 2016 Accepted: August 25, 2016 Published: September 12, 2016
https://doi.org/10.18632/aging.101032How to Cite
Abstract
Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant. We found that oligodendrocyte progenitor cell proliferation and oligodendrocyte density is markedly reduced in mutant mice with low amounts of BubR1 (BubR1H/H mice), causing axonal hypomyelination in both brain and spinal cord. Expression of essential myelin-related genes such as MBP and PLP1 was significantly reduced in these tissues. Consistent with defective myelination, BubR1H/H mice exhibited various motor deficits, including impaired motor strength, coordination, and balance, irregular gait patterns and reduced locomotor activity. Collectively, these data suggest that BubR1 is a key determinant of oligodendrocyte production and function and provide a molecular entry point to understand age-related degenerative changes in axon myelination.