Myelin lipids are energy reserves in the nervous system
by Ebrahim Asadollahi
Date of Examination:2020-04-17
Date of issue:2021-03-18
Advisor:Prof. Dr. Klaus-Armin Nave
Referee:Prof. Dr. Klaus-Armin Nave
Referee:Prof. Dr. Peter Schu
Referee:Dr. Nuno Raimundo
Referee:Prof. Dr. Martin Göpfert
Referee:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Ralf Heinrich
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Abstract
English
Neuronal functions critically depend on a continuous supply of glucose as prolonged hypoglycemia can lead to severe brain injury. It is surprising that except for astroglial glycogen the brain has no visible energy reserves. Myelin is a lipid-rich membrane that enwraps axons for fast impulse conduction. Myelinating oligodendrocytes also provide metabolic support to axons. We thus hypothesized that under starvation conditions myelin itself might support the white matter energy balance. Using the mouse optic nerve as a model, we found that oligodendrocytes but not astrocytes survive glucose deprivation ex vivo for up to 24 hours. In addition, myelin thickness was observed to decrease under starvation conditions and beta-oxidation inhibition was shown to induce massive cell death in the optic nerve. These observations suggest fatty acids (FAs) released from myelin are involved in supporting cell survival under starvation Importantly, using electrophysiology combined with live imaging we showed that FA metabolism supports axonal ATP production and nerve conduction by perturbing beta-oxidation. This axonal support depends on FA beta-oxidation involving peroxisomes in the myelin compartment. To study reduced glucose availability in live mice, we deleted GLUT1 (Slc2a1) from mature oligodendrocytes, which led to slowly progressive loss of myelin. We therefore suggest a revised model for the dual function of oligodendrocytes, with myelin constituting an energy buffer that can prevent axonal degeneration when glucose availability is perturbed. These findings may be relevant for myelin abnormalities found in a range of neurodegenerative disease.
Keywords: Myelin; Fatty acids; Beta-oxidation; Mitochondria; Nervous system; oligodendrocyte; Energy reserves; Peroxisome