Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice

Gargareta, Vasiliki-Ilya; Reuschenbach, Josefine; Siems, Sophie B; Sun, Ting; Piepkorn, Lars; Mangana, Carolina; Späte, Erik; Goebbels, Sandra; Huitinga, Inge; Möbius, Wiebke; Nave, Klaus Armin; Jahn, Olaf; Werner, Hauke

doi:10.7554/elife.77019

Cited by 36 publications

(21 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To this aim, we surveyed the “BioGrid” protein–protein interaction database [ 31 ] and extracted the currently known list of experimentally demonstrated NDRG1 protein partners ( Table S7 ). Taking advantage of a recent study mapping the human CNS myelin proteome [ 32 ], we then crossed the NDRG1 interactome with the human myelin proteome ( Table S7 ). Interestingly, the list of NDRG1 protein partners was found to be highly significantly enriched in human myelin proteins (enrichment factor 6.24; p -value: 1.59 × 10 −40 ) ( Table S7 ).…”

Section: Resultsmentioning

confidence: 99%

Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature

Nataf

Guillen

Pays

2022

IJMS

View full text Add to dashboard Cite

In a substantial share of patients suffering from multiple sclerosis (MS), neurological functions slowly deteriorate despite a lack of radiological activity. Such a silent progression, observed in either relapsing-remitting or progressive forms of MS, is driven by mechanisms that appear to be independent from plaque activity. In this context, we previously reported that, in the spinal cord of MS patients, periplaques cover large surfaces of partial demyelination characterized notably by a transforming growth factor beta (TGF-beta) molecular signature and a decreased expression of the oligodendrocyte gene NDRG1 (N-Myc downstream regulated 1). In the present work, we re-assessed a previously published RNA expression dataset in which brain periplaques were originally used as internal controls. When comparing the mRNA profiles obtained from brain periplaques with those derived from control normal white matter samples, we found that, irrespective of plaque activity, brain periplaques exhibited a TGF-beta molecular signature, an increased expression of TGFB2 (transforming growth factor beta 2) and a decreased expression of the oligodendrocyte genes NDRG1 (N-Myc downstream regulated 1) and MAG (myelin-associated glycoprotein). From these data obtained at the mRNA level, a survey of the human proteome allowed predicting a protein–protein interaction network linking TGFB2 to the down-regulation of both NDRG1 and MAG in brain periplaques. To further elucidate the role of NDRG1 in periplaque-associated partial demyelination, we then extracted the interaction network linking NDRG1 to proteins detected in human central myelin sheaths. We observed that such a network was highly significantly enriched in RNA-binding proteins that notably included several HNRNPs (heterogeneous nuclear ribonucleoproteins) involved in the post-transcriptional regulation of MAG. We conclude that both brain and spinal cord periplaques host a chronic process of tissue remodeling, during which oligodendrocyte myelinating functions are altered. Our findings further suggest that TGFB2 may fuel such a process. Overall, the present work provides additional evidence that periplaque-associated partial demyelination may drive the silent progression observed in a subset of MS patients.

show abstract

Section: Resultsmentioning

confidence: 99%

Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature

Nataf

Guillen

Pays

2022

IJMS

View full text Add to dashboard Cite

show abstract

“…This may indicate that surface trafficking of metabolite transporters in OLs is modulated by K + and Kir4.1-mediated signaling. Interestingly, proteome analysis of optic nerve lysates showed a reduction in proteins involved in intracellular membrane trafficking, including vesicle associated membrane proteins VAMP2 and VAMP3, as well as the small GTPases RAB2B and RAB5A, all of which are expressed by mature OLs [84][85][86] . While the molecular machinery regulating surface trafficking of metabolite transporters in OLs is still poorly understood, studies on adipocytes showed that VAMP2 and RAB5 family of GTPases are involved in GLUT4 glucose transporter trafficking [87][88][89] .…”

Section: Discussionmentioning

confidence: 99%

Potassium regulates axon-oligodendrocyte signaling and metabolic coupling in white matter

Looser

Ravotto

Jung³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs), which is essential for brain function. However, the mechanisms by which OLs detect axonal spiking and rapidly control axon-OL metabolic coupling are largely unknown. Here, we combine optic nerve electrophysiology and two-photon imaging to study activity-dependent calcium (Ca2+) dynamics in OLs and metabolite fluxes in myelinated axons. Both high-frequency axonal firing and extracellular potassium (K+) elevations trigger a fast Ca2+response in OLs that is facilitated by barium-sensitive, inwardly rectifying K+channels. Using OL-specific Kir4.1 knockout mice (Kir4.1 cKO) we now demonstrate that, in addition to being crucial for K+clearance, oligodendroglial Kir4.1 regulates axonal energy metabolism and long-term axonal integrity. Before the manifestation of axonal damage, we observed reduced glucose transporter GLUT1 and monocarboxylate transporter MCT1 expression in myelin of young Kir4.1 cKO mice, suggesting early deficits in metabolite supply to axons. Strikingly, we found lower resting lactate levels and activity-induced lactate surges in optic nerve axons of young Kir4.1 cKO mice. Moreover, both axonal glucose uptake and consumption were hampered in the absence of oligodendroglial Kir4.1, uncovering a new role of OLs in regulating axonal glucose metabolism. Our findings reveal a novel model of axon-OL signaling and metabolic coupling in which OLs detect high-frequency axonal activity through K+signaling, which is critical in adjusting the axon-OL metabolic unit and in preserving long-term axonal health.

show abstract

“…Additionally, although rodent models are commonly used to study the pathophysiology of human diseases, previous studies have demonstrated the difference between rodent and human nervous systems. For example, proteome and transcriptome studies identified multiple proteins exclusively or predominantly in human or mouse CNS myelin [ 61 ]. Even though both rat and human Schwann cells will proliferate in response to the axonal mitogen neuregulin, only the rat Schwann cells will efficiently ensheath and myelinate axons in vitro [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Distinct Changes in Calpain and Calpastatin during PNS Myelination and Demyelination in Rodent Models

Miller

Drouet

Yermakov

et al. 2022

IJMS

View full text Add to dashboard Cite

Myelin forming around axons provides electrical insulation and ensures rapid and efficient transmission of electrical impulses. Disruptions to myelinated nerves often result in nerve conduction failure along with neurological symptoms and long-term disability. In the central nervous system, calpains, a family of calcium dependent cysteine proteases, have been shown to have a role in developmental myelination and in demyelinating diseases. The roles of calpains in myelination and demyelination in the peripheral nervous system remain unclear. Here, we show a transient increase of activated CAPN1, a major calpain isoform, in postnatal rat sciatic nerves when myelin is actively formed. Expression of the endogenous calpain inhibitor, calpastatin, showed a steady decrease throughout the period of peripheral nerve development. In the sciatic nerves of Trembler-J mice characterized by dysmyelination, expression levels of CAPN1 and calpastatin and calpain activity were significantly increased. In lysolecithin-induced acute demyelination in adult rat sciatic nerves, we show an increase of CAPN1 and decrease of calpastatin expression. These changes in the calpain-calpastatin system are distinct from those during central nervous system development or in acute axonal degeneration in peripheral nerves. Our results suggest that the calpain-calpastatin system has putative roles in myelination and demyelinating diseases of peripheral nerves.

show abstract

Conservation and divergence of myelin proteome and oligodendrocyte transcriptome profiles between humans and mice

Cited by 36 publications

References 72 publications

Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature

Irrespective of Plaque Activity, Multiple Sclerosis Brain Periplaques Exhibit Alterations of Myelin Genes and a TGF-Beta Signature

Potassium regulates axon-oligodendrocyte signaling and metabolic coupling in white matter

Distinct Changes in Calpain and Calpastatin during PNS Myelination and Demyelination in Rodent Models

Contact Info

Product

Resources

About