MyeliNANO · Myelinic nanochannels in neurodegenerative diseases

Myelin is made by highly specialized glial cells and enables fast axonal impulse propagation. We havediscovered that oligodendrocytes in the CNS are, in addition to myelination, required for the integrity andsurvival of axons, independent of the presence or absence of myelin itself. More recently, we found theunderlying mechanism and could show that glycolytic oligodendrocytes provide axons with pyruvate/lactate.These metabolites are transported through a system of myelinic nanochannels to the axonal compartment, inwhich mitochondria generate ATP. The finding was a paradigm-shift for the physiological function of axonassociatedglia, and opens now the intriguing possibility that oligodendrocytes are important modifiers ofneurological diseases in which myelinated axons are lost. This includes, in addition to multiple sclerosis, alsoclassical neuropsychiatric disorders. We will generate novel genetic tools in mice that allow us to study therole myelin and secondary axonal loss in higher brain functions. We will test the challenging hypothesis thatreducing oligodendroglial support of axonal metabolism is a risk for differen neurodegenerative disorders.These involve the previously neglected ultrastructure of CNS myelin with cytosolic (20-300 nanometerwide) channels within the myelin sheath. These 'nanochannels' couple the oligodendrocyte somametabolically to the adaxonal space, but are vulnerable to aging and physical injury. We hypothesize thatcellular mechanisms as diverse as neuroinflammation and the aggregation of misfolded proteins in myelinicnanochannels cause perturbations of the axonal energy metabolism. When combined, the findings ofMyeliNANO will shed new light on previously unknown functions of CNS myelin and will pave the way formetabolic neuroprotection as a therapeutic approach to a range of neurodegenerative diseases.