White matter integrity requires continuous myelin synthesis at the inner tongue

Abstract

SummaryMyelin, the electrically insulating axonal sheath, is composed of lipids and proteins with exceptionally long lifetime. This raises the question how myelin function is affected by myelin turnover. We have studied the integrity of myelinated tracts after experimentally preventing the formation of new myelin in the CNS of adult mice, using an inducible Mbp null allele. Oligodendrocytes survived recombination, continued expressing myelin genes, but failed to maintain compacted myelin sheaths. Using 3D electron microscopy and mass spectrometry imaging we visualized myelin-like membranes that failed to incorporate adaxonally, most prominently at juxta-paranodes. Myelinoid body formation indicated degradation of existing myelin at the abaxonal side and at the inner tongue of the sheath. Compacted myelin thinning and shortening of internodes, with about 50% myelin lost after 20 weeks (=5 months), ultimately led to axonal pathology and neurological disease. These data reveal that functional axon-myelin units require the continuous incorporation of new myelin membranes.

Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis

“…2e , Supplementary Table 2 ). Myelin disease, whether induced pharmacologically (6w and 12+2w cuprizone), genetically (MBPcKO, inducible myelin basic protein (MBP) mutant 14 ) or by autoimmunity (EAE, experimental autoimmune encephalomyelitis), was always associated with downregulation of sterol gene transcripts in astrocytes ( Fig. 1d, 1f , Extended Data Fig.…”

Tbx1, a 22q11.2-encoded gene, is a link between alterations in fimbria myelination and cognitive speed in mice

“…4BC ). MBP is essential for the maintenance of myelin and is involved in the adhesion and compaction of the cytosolic membrane leaflets that form the structural basis of multilayered myelin ( 41, 42 ). Myelin oligodendrocyte glycoprotein (MOG) is a marker of mature oligodendrocytes and myelin, although it is not functionally critical for myelin formation or maintenance ( 43 ).…”

mTORC1 and JUN are activated after deletion of Prohibitin 1 in Schwann cells and may link mitochondrial dysfunction to demyelination

“…Although little is known about how myelin is maintained long-term, it seems that preservation of myelin with the correct structure and thickness is an active process, requiring the continuous activation of certain cellular machinery in SCs (Bremer et al, 2010, Zhou et al, 2020, Meschkat et al, 2020, Bremer et al, 2011, Decker et al, 2006). We therefore hypothesized that the SC response to mitochondrial dysfunction may inadvertently interfere with pathways critical for myelin maintenance.…”

“…Nevertheless, even early studies were quick to point out that some of the myelin components had much faster turnover rates (Singh and Jungalwala, 1979, Sabri et al, 1974, Hayes and Jungalwala, 1976), suggesting that portions of the myelin (especially its non-compact regions) could be more dynamic. Furthermore, we now know that maintenance of the myelin structure is not passive, requiring sustained expression of the transcription factors EGR2 (also known as Krox20) (Decker et al, 2006) and SOX10 (Bremer et al, 2011) in SCs, as well as continuous synthesis of myelin proteins (Meschkat et al, 2020) and lipids (Zhou et al, 2020) in brain.…”