Elucidating the Trophic Support of Long Axons by Metabolic Signaling in Oligodendrocytes

The fundamenal neuroscientific question as to how myelinating glia promote the health of long
axons is greatly understudied. Axons are a particularly vulnerable component of neural circuits
that are irreversibly damaged in early stages of many debilitating neurodegenerative conditions
such as Multiple sclerosis and Alzheimers’ disease. The mechanisms underlying glial
contributions to axonal injury are only pooly understood. Oligodendrocytes (OLGs), the
myelinating glia of the central nervous system, stabilize axonal integrity by poorly understood
trophic mechanisms. Current models suggest that glial metabolism is critical for this support
function, and disrupted metabolic exchange between OLGs and axons, or metabolic deficits in
OLGs may lead to axonal degeneration. In support, we made the exciting discovery that the LKB1
(liver kinase B1) signaling pathway is a crucial metabolic regulator in OLGs, and the inactivation
of LKB1 in these glia results in aberrant mitochondrial energy metabolism and progressive
degeneration of axons. Remarkably, such non-cell-autonomous axon degeneration is not
preceded by changes of OLG structure and myelination, indicating that it occurs secondary to
glial metabolic perturbation. These discoveries lead us to hypothesize that LKB1 and its
downstream metabolic effectors, most notably those regulating mitochondrial metabolism in
OLGs, are integral to the trophic support mechanisms for axons. Using manipulation of LKB1
signaling as an experimental tool to change glial metabolism with no impact on other biological
outputs of OLGs, here we implement a multidisciplinary approach that will afford us the unique
opportunity to pinpoint metabolic alterations in OLGs that disrupt the support of axons. In this
context we will also investigate whether axons degenerate as a consequence of energetic
deprivation, or metabolic poisoining. Together, this will provide valuable data to elucidate which
downstream components of the LKB1-dependent metabolic signaling network in OLGs are
fundamentally important for axon integrity. The proposed efforts may open the door to the
identification of unexpected metabolic components in OLGs that are essential for axon support.
Manipulation of these components will have the potential to promote axon integrity in
neurodegenerative diseases. Because glial and metabolic abnormalities associated with axon
degeneration can be observed in many neurodegenerative conditions, this approach has the
potential for wide-ranging therapeutic impact.

Grant Number: 5R01NS111024-05
NIH Institute/Center: NIH
Principal Investigator: Bogdan Beirowski