Structural myelin defects are associated with low axonal ATP levels but rapid recovery from energy deprivation in a mouse model of spastic paraplegia

Abstract

In several neurodegenerative disorders, axonal pathology may originate from impaired oligodendrocyte-to-axon support of energy substrates. We previously established transgenic mice that allow measuring axonal ATP levels in electrically active optic nerves. Here, we utilize this technique to explore axonal ATP dynamics in the Plpnull/y mouse model of spastic paraplegia. Optic nerves from Plpnull/y mice exhibited lower and more variable basal axonal ATP levels and reduced compound action potential (CAP) amplitudes, providing a missing link between axonal pathology and a role of oligodendrocytes in brain energy metabolism. Surprisingly, when Plpnull/y optic nerves are challenged with transient glucose deprivation, both ATP levels and CAP decline slower, but recover faster upon reperfusion of glucose. Structurally, myelin sheaths display an increased frequency of cytosolic channels comprising glucose and monocarboxylate transporters, possibly facilitating accessibility of energy substrates to the axon. These data imply that complex metabolic alterations of the axon–myelin unit contribute to the phenotype of Plpnull/y mice.

The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

“…Both mutant mice and over-expressors exhibited significantly smaller axons, while the axons in the over-expressors had significantly thinner myelin sheaths. More surprisingly, however, mice over-expressing TMEM 135 exhibited separation of the myelin sheath from some axons ( Figure 7 ), an architecture that has also been reported in models of Charcot–Marie–Tooth syndrome [ 165 ] and in the optic nerves of Plp null/y mice, a model of spastic paraplegia [ 166 ]. In the latter, myelination defects were found to be associated with lower axonal levels of ATP [ 166 ], consistent with the evidence that Tmem135 over-expressors may have reduced capacity for oxidative phosphorylation.…”

Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice

“…Even subtle myelin defects can lead to axonal damage, myelin instability, and glial activation, as observed in null mutants of the myelin-specific genes Plp1 (proteolipid protein 1) and Cnp1 (2 0 ,3 0 -cyclic-nucleotide 3 0 -phosphodiesterase) (Edgar et al, 2004(Edgar et al, , 2009Lappe-Siefke et al, 2003;Trevisiol et al, 2020). To assess neuronal responses to mild alterations in myelin integrity, we genetically labeled neuronal nuclei, predominantly of callosal projection neurons (CPNs) in Plp1 and Cnp1 knockout mice, with the Thy1-EYFPnuc transgene (Wehr et al, 2006).…”

Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5

“…The axonopathy observed upon deleting Cmtm5 strongly implies that CMTM5 is involved in the oligodendroglial function of preserving axonal integrity and that this function is not limited to an early developmental stage. Oligodendroglial support of axons involves several mechanisms, including supplying energy-rich substrates via monocarboxylate transporters (Fünfschilling et al, 2012;Lee et al, 2012;Philips et al, 2021;Trevisiol et al, 2020), allocating antioxidative proteins and other enzymes via extracellular vesicles (Chamberlain et al, 2021;Frühbeis et al, 2020;Mukherjee et al, 2020), and modulating axonal transport (Edgar et al, 2004;Frühbeis et al, 2020), these mechanisms being possibly interrelated. It will be an important next step to identify the specific mechanism(s) of axonal support that are impaired when oligodendrocytes lack CMTM5.…”

“…This indicates that the lack of myelin per se is less detrimental for axons than axonal ensheathment with functionally impaired myelin. Moreover, APPimmunopositive axonal swellings, astrogliosis and microgliosis are early features when PLP (Griffiths et al, 1998;de Monasterio-Schrader et al, 2013;Edgar et al, 2004;Steyer et al, 2020;Trevisiol et al, 2020) or CNP (Edgar et al, 2009;Lappe-Siefke et al, 2003;Wieser et al, 2013) are lacking, but emerges at much older age in CMTM5-deficient mice. This indicates that the pathomechanisms differ between Plp1 and Cnp-mutants and Cmtm5-mutants.…”