Dataset Information

MAG induces apoptosis in cerebellar granule neurons through p75^NTR demarcating granule layer/white matter boundary.

ABSTRACT: MAG (Myelin-associated glycoprotein) is a type I transmembrane glycoprotein expressed by Schwann cells and oligodendrocytes, that has been implicated in the control of axonal growth in many neuronal populations including cerebellar granule neurons (CGNs). However, it is unclear whether MAG has other functions in central nervous system, in particular, in cerebellar development and patterning. We find that MAG expression in the cerebellum is compartmentalised resulting in increased MAG protein levels in the cerebellar white matter. MAG induces apoptosis in developing CGNs through p75^NTR signalling. Deletion of p75^NTR in vivo reduced the number of apoptotic neurons in cerebellar white matter during development leading to reduction in the size of white matter in the adulthood. Furthermore, we show that MAG impairs CGNs neurite outgrowth as consequence of MAG-induced apoptosis in CGNs. Mechanistically, we find that MAG/NgR1-induced cell death is dependent of p75^NTR-mediated activation of JNK/cell death signalling pathway. Together, these findings identify the mechanisms by which MAG induces CGNs apoptotic activity, a crucial event that facilitates cerebellar layer refinement during development.

SUBMITTER: Fernandez-Suarez D

PROVIDER: S-EPMC6768859 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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MAG induces apoptosis in cerebellar granule neurons through p75<sup>NTR</sup> demarcating granule layer/white matter boundary.

Fernández-Suárez Diana D Krapacher Favio A FA Andersson Annika A Ibáñez Carlos F CF Kisiswa Lilian L

Cell death & disease 20190930 10

MAG (Myelin-associated glycoprotein) is a type I transmembrane glycoprotein expressed by Schwann cells and oligodendrocytes, that has been implicated in the control of axonal growth in many neuronal populations including cerebellar granule neurons (CGNs). However, it is unclear whether MAG has other functions in central nervous system, in particular, in cerebellar development and patterning. We find that MAG expression in the cerebellum is compartmentalised resulting in increased MAG protein lev ...[more]

PMID: 31570696

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Project description:ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.

Dataset Information

MAG induces apoptosis in cerebellar granule neurons through p75^NTR demarcating granule layer/white matter boundary.

Publications

MAG induces apoptosis in cerebellar granule neurons through p75<sup>NTR</sup> demarcating granule layer/white matter boundary.

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Dataset Information

MAG induces apoptosis in cerebellar granule neurons through p75NTR demarcating granule layer/white matter boundary.

Publications

MAG induces apoptosis in cerebellar granule neurons through p75<sup>NTR</sup> demarcating granule layer/white matter boundary.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

MAG induces apoptosis in cerebellar granule neurons through p75^NTR demarcating granule layer/white matter boundary.