Aging of myelinating glial cells predominantly affects lipid metabolism and immune response pathways

Abstract

Both the central and the peripheral nervous systems are prone to multiple age-dependent neurological deficits, often attributed to still unknown alterations in the function of myelinating glia. To uncover the biological processes affected in glial cells by aging, we analyzed gene expression of the Schwann cell-rich mouse sciatic nerve at 17 time points throughout life, from day of birth until senescence. By combining these data with the gene expression data of myelin mouse mutants carrying deletions of either Pmp22, SCAP, or Lpin1, we found that the majority of age-related transcripts were also affected in myelin mutants (54.4%) and were regulated during PNS development (59.5%), indicating a high level of overlap in implicated molecular pathways. The expression profiles in aging copied the direction of transcriptional changes observed in neuropathy models; however, they had the opposite direction when compared with PNS development. The most significantly altered biological processes in aging involved the inflammatory/immune response and lipid metabolism. Interestingly, both these pathways were comparably changed in the aging optic nerve, suggesting that similar biological processes are affected in aging of glia-rich parts of the central and peripheral nervous systems. Our comprehensive comparison of gene expression in three distinct biological conditions including development, aging, and myelin disease thus revealed a previously unanticipated relationship among themselves and identified lipid metabolism and inflammatory/immune response pathways as potential therapeutical targets to prevent or delay so far incurable age-related and inherited forms of neuropathies.

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

“…Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org). Several resources are available to identify SC-specific genes, including (1) expression profiles of peripheral nerve development and response to injury, [37][38][39][40][41][42][43][44] (2) profiling of sorted cell types in mouse embryonic skin, 30 and (3) RNA-seq profiling of >400 human tibial nerve samples, 45 along with many other tissues (Broad Institute; gtexportal.org).…”

A role of peripheral myelin protein 2 in lipid homeostasis of myelinating schwann cells

“…1a). Next, we compared Pmp2 expression with two major peripheral myelin proteins, Mbp and Mpz, in sciatic nerve endoneurium during mouse peripheral nerve development, maintenance and ageing (P0 to 28 months of age), using a previously published microarray study (Verdier et al, 2012) (Fig. 1b).…”

Dietary restriction supports peripheral nerve health by enhancing endogenous protein quality control mechanisms

“…Starting at the level of gene activation, recent studies have identified transcriptional alterations in aged Schwann cells, with the most significant changes occurring in genes encoding proteins that regulate lipid metabolism or the inflammatory response (Verdier et al, 2012). Indeed, damage to myelin is associated with an elevated immune response, and infiltration of circulating macrophages was observed in nerves of aged, as well as neuropathic rodents (Misko et al, 2002; Opalach et al, 2010).…”