Descrizione del progetto
La mielina, un protagonista nella neurodegenerazione?
I neuroni presenti nel cervello e nel midollo spinale sono isolati da una guaina mielinica che può aumentare notevolmente la velocità degli impulsi elettrici. La mielina viene prodotta dagli oligodendrociti, che sembrano svolgere un ruolo centrale nell’integrità dei neuroni fornendo i metaboliti essenziali necessari per la produzione di energia neuronale. Questa funzione suggerisce che tali cellule potrebbero esercitare un impatto sui disturbi neurologici legati alla demielinizzazione, come la sclerosi multipla. Finanziato dal Consiglio europeo della ricerca, il progetto MyeliNANO mira a studiare il ruolo svolto dalla mielina nelle funzioni cerebrali superiori e la misura in cui gli oligodendrociti influiscono sull’integrità funzionale dei neuroni e sulla neurodegenerazione. I risultati apriranno la strada alla neuroprotezione metabolica quale potenziale strategia terapeutica per le malattie neurodegenerative.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
80539 Munchen
Germania