How Does Protein Zero Assemble Compact Myelin?

Raasakka, Arne; Kursula, Petri

doi:10.20944/preprints202005.0222.v1

Cited by 8 publications

(5 citation statements)

References 140 publications

(281 reference statements)

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“…We used C57BL/6-Tg(Uchl1-EGFP)G1Phoz/J mice which endogenously express a pan-neuronal GFP reporter (henceforth referred to as PGP9.5-EGFP +/- ) to investigate the relative proportions of myelinated and non-myelinated nerves in inguinal scWAT (Figure 1A-C). To label the myelin sheath of adipose-resident peripheral nerves, we used antibodies against two myelin specific proteins, MPZ that is more commonly found in the PNS, and MBP that is more commonly found in the CNS but also localized to PNS myelin [21]. Co-expression of PGP9.5-EGFP +/- with either MPZ or MBP was interpreted as a myelinated fiber and the absence of either marker on a PGP9.5-EGFP +/- nerve was interpreted as a non-myelinated fiber.…”

Section: Resultsmentioning

confidence: 99%

The Presence of Myelinated Nerves and Schwann Cells in White Adipose Tissue: Proximity to Synaptic Vesicle Containing Nerve Terminals and Potential Role in BTBR ob/ob Demyelinating Diabetic Neuropathy

Willows

Gunsch

Paradi

et al. 2022

Preprint

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Peripheral neuropathy is a pathophysiological state of nerve degeneration and loss of tissue innervation. The most prominent cause of small fiber neuropathy is diabetes which can be demyelinating in nature, but this has not yet been explored in adipose tissue. Both demyelinating neuropathies and axonopathies implicate Schwann cells (SCs), the peripheral glial required for nerve myelination and regeneration after injury. Here, we perform a comprehensive assessment of SCs and myelination patterns of subcutaneous white adipose tissue (scWAT) nerves, including changes that occur with obesity and other imbalanced energy states in mice and humans. We found that mouse scWAT is densely innervated by both myelinated and unmyelinated sensory and sympathetic nerves. Accordingly, scWAT is home to both myelinating and non-myelinating SCs; the greater proportion of which are myelinating. Furthermore, SCs were found closely associated with synaptic vesicle-containing nerve terminals in scWAT. Obese BTBR ob/ob mice exhibit diabetic peripheral neuropathy in scWAT, and display concordant demyelination specific to small fibers, which was also associated with a decrease in the pan-SC marker Sox10 and compensatory increase in Krox20 gene expression. Together this suggests that adipose SCs may be involved in regulating the plasticity or the neuropathy of adipose tissue nerves.

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Section: Resultsmentioning

confidence: 99%

The Presence of Myelinated Nerves and Schwann Cells in White Adipose Tissue: Proximity to Synaptic Vesicle Containing Nerve Terminals and Potential Role in BTBR ob/ob Demyelinating Diabetic Neuropathy

Willows

Gunsch

Paradi

et al. 2022

Preprint

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“…For both MBP and P0ct, data from various biophysical experiments have been published [33,41,[48][49][50][51][52][53], showing folding of both proteins upon membrane binding, while they remain unfolded in aqueous solution. The regions binding to membranes have been mapped to specific segments, mainly those prone to fold into helices according to predictions.…”

Section: Resultsmentioning

confidence: 99%

“…P0 molecules are believed to oligomerize between proteins located on apposing membranes [68], via both the extracellular and intracellular domains. The cytoplasmic domain P0ct is not only important for membrane stacking at the PNS major dense line, but given its nature as part of a transmembrane protein, it could be involved in P0 trafficking, which further is regulated by post-translational modifications in the P0ct [51].…”

Section: The Cytoplasmic Domain Of P0 -Similar But Different To Mbpmentioning

confidence: 99%

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The intrinsically disordered protein glue of myelin: Linking AlphaFold2 predictions to experimental data

Krokengen

Raasakka

Kursula

2022

Preprint

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Numerous human proteins are either partially or fully classified as intrinsically disordered proteins (IDPs). Due to their properties, high-resolution structural information about IDPs is generally lacking. On the other hand, IDPs are known to adopt local ordered structures upon interactions with ligands, which could be e.g. other proteins or lipid membrane surfaces. While recent developments in protein structure prediction have been revolutionary, their impact on IDP research at high resolution remains limited. We took a specific example of two myelin-specific IDPs, the myelin basic protein (MBP) and the cytoplasmic domain of myelin protein zero (P0ct). Both of these IDPs are known to be crucial for normal nervous system development and function, and while they are disordered in solution, upon membrane binding, they partially fold into helices, being embedded into the lipid membrane. We carried out AlphaFold2 predictions of both proteins and analysed the models in light of previously published data related to solution structure and molecular interactions. We observe that the predicted models have helical segments that closely correspond to the characterised membrane-binding sites on both proteins. Hence, artificial intelligence-based models of IDPs appear to be able to provide detailed information on the ligand-bound state of these proteins, instead of the form dominating free in solution. We further discuss the implications of the predictions for normal mammalian nervous system myelination and their relevance to understanding disease aspects of these IDPs.

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“…MPZ, or P0, is a transmembrane protein responsible for compaction of cell membranes in the myelin of peripheral nerves. 21 It is expressed at lower levels in the membranes of non-myelinating Schwann cells, 22 but it is purportedly not expressed in intrinsic enteric glial cells. 23 With an MPZ-specific chicken antibody, Woods et al 23 demonstrated intense immunofluorescent labeling of extrinsic nerves in the mesorectum and myenteric plexus in frozen sections of normal human cadaveric rectal tissue, but no immunoreactivity in intrinsic nerves in the submucosa or mucosa.…”

Section: Introductionmentioning

confidence: 99%

Myelin Protein Zero Immunohistochemistry Is Not a Reliable Marker of Extrinsic Mucosal Innervation in Patients With Hirschsprung Disease

2021

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Background Innervation of aganglionic rectum in Hirschsprung disease derives from extrinsic nerves which project from cell bodies located outside the bowel wall and markers that distinguish extrinsic from intrinsic innervation are diagnostically useful. Myelin protein zero (MPZ) is a putative marker of extrinsic glial cells which could distinguish mucosal innervation in aganglionic vs ganglionic colon. Methods Sections and protein blots from ganglionic and aganglionic colon were immunolabeled with MPZ-specific antibodies. Results Immunolabeling of MPZ with a chicken polyclonal or mouse monoclonal antibody confirmed glial specificity and reliably labeled hypertrophic submucosal nerves in Hirschsprung disease. In contrast, a rabbit polyclonal antibody strongly labeled extrinsic and intrinsic nerves, including most mucosal branches. Immunoblots showed MPZ is expressed in mucosal glial cells, albeit at lower levels than in extrinsic nerves, and that the rabbit antibody is more sensitive that the other two probes. Unfortunately, none of these antibodies consistently distinguished mucosal innervation in aganglionic vs ganglionic rectum Conclusions The results suggest that (a) glial cell myelin protein zero expression is influenced more by location (mucosa vs submucosa) than the extrinsic vs intrinsic origin of the accompanied nerves and (b) myelin protein zero immunohistochemistry has limited value as a diagnostic adjunct for Hirschsprung disease.

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How Does Protein Zero Assemble Compact Myelin?

Cited by 8 publications

References 140 publications

The Presence of Myelinated Nerves and Schwann Cells in White Adipose Tissue: Proximity to Synaptic Vesicle Containing Nerve Terminals and Potential Role in BTBR ob/ob Demyelinating Diabetic Neuropathy

The Presence of Myelinated Nerves and Schwann Cells in White Adipose Tissue: Proximity to Synaptic Vesicle Containing Nerve Terminals and Potential Role in BTBR ob/ob Demyelinating Diabetic Neuropathy

The intrinsically disordered protein glue of myelin: Linking AlphaFold2 predictions to experimental data

Myelin Protein Zero Immunohistochemistry Is Not a Reliable Marker of Extrinsic Mucosal Innervation in Patients With Hirschsprung Disease

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