Project description
Myelin: key player in neurodegeneration?
Neurons in the brain and spinal cord are insulated by a myelin sheath which can greatly increase the speed of electrical impulses. Myelin is produced by oligodendrocytes which seem to play a central role in neuron integrity by providing essential metabolites required for neuronal energy production. This suggests that oligodendrocytes could impact neurological disorders involving demyelination, such as multiple sclerosis. Funded by the European Research Council, the MyeliNANO project aims to investigate the role of myelin in higher brain functions and the extent to which oligodendrocytes impact functional integrity of neurons and neurodegeneration. Results will pave the way for metabolic neuroprotection as a potential therapeutic strategy for neurodegenerative diseases.
Objective
Myelin is made by highly specialized glial cells and enables fast axonal impulse propagation. We have
discovered that oligodendrocytes in the CNS are, in addition to myelination, required for the integrity and
survival of axons, independent of the presence or absence of myelin itself. More recently, we found the
underlying 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, in
which mitochondria generate ATP. The finding was a paradigm-shift for the physiological function of axonassociated
glia, and opens now the intriguing possibility that oligodendrocytes are important modifiers of
neurological diseases in which myelinated axons are lost. This includes, in addition to multiple sclerosis, also
classical neuropsychiatric disorders. We will generate novel genetic tools in mice that allow us to study the
role myelin and secondary axonal loss in higher brain functions. We will test the challenging hypothesis that
reducing 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 nanometer
wide) channels within the myelin sheath. These 'nanochannels' couple the oligodendrocyte soma
metabolically to the adaxonal space, but are vulnerable to aging and physical injury. We hypothesize that
cellular mechanisms as diverse as neuroinflammation and the aggregation of misfolded proteins in myelinic
nanochannels cause perturbations of the axonal energy metabolism. When combined, the findings of
MyeliNANO will shed new light on previously unknown functions of CNS myelin and will pave the way for
metabolic neuroprotection as a therapeutic approach to a range of neurodegenerative diseases.
Fields of science
- medical and health sciencesbasic medicineneurologydementiaalzheimer
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicineimmunologyimmunisation
- medical and health sciencesbasic medicineneurologymultiple sclerosis
- medical and health sciencesbasic medicineneurologyamyotrophic lateral sclerosis
Programme(s)
Topic(s)
Funding Scheme
ERC-ADG - Advanced GrantHost institution
80539 Munchen
Germany