Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects

Author:

Groh JanosORCID,Abdelwahab TassnimORCID,Kattimani Yogita,Hörner MichaelaORCID,Loserth Silke,Gudi Viktoria,Adalbert Robert,Imdahl Fabian,Saliba Antoine-EmmanuelORCID,Coleman MichaelORCID,Stangel Martin,Simons MikaelORCID,Martini RudolfORCID

Abstract

AbstractAxon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

Funder

Deutsche Forschungsgemeinschaft

Gemeinnützige Hertie-Stiftung

Roman, Marga und Mareille Sobek Foundation; Interdisciplinary Centre for Clinical Research of the University of Würzburg

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Axon, “axoff”;Science Signaling;2023-11-07

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