Cuprizone-induced graded oligodendrocyte vulnerability is regulated by the transcription factor DNA damage-inducible transcript 3

Autor: Tim Clarner, Christian Beißel, Anand Goswami, Felix Fischbach, Christoph Schmitz, Patrizia Leopold, Marion Victor, Cordian Beyer, Tanja Hochstrasser, Yasemin van Heuvel, Lara Nellessen, Joachim Weis, Jiangshan Zhan, Julia Nedelcu, Stella Nyamoya, Bernd Denecke, Markus Kipp
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Monoamine Oxidase Inhibitors
Mice
Transgenic
Nerve Tissue Proteins
DNA damage-inducible transcript 3
Biology
Microgliosis
Corpus Callosum
03 medical and health sciences
Cellular and Molecular Neuroscience
Cuprizone
Mice
0302 clinical medicine
medicine
Animals
Demyelinating Disorder
Transcription factor
Cells
Cultured
Multiple sclerosis
Calcium-Binding Proteins
Microfilament Proteins
medicine.disease
Endoplasmic Reticulum Stress
Oligodendrocyte
Cell biology
Mice
Inbred C57BL
Disease Models
Animal
Oligodendroglia
030104 developmental biology
medicine.anatomical_structure
Neurology
Animals
Newborn
Gene Expression Regulation
Astrocytes
Unfolded protein response
Microscopy
Electron
Scanning
Astrocytosis
030217 neurology & neurosurgery
Transcription Factor CHOP
Demyelinating Diseases
Zdroj: Glia. 67(2)
ISSN: 1098-1136
Popis: Oligodendrocytes are integral to efficient neuronal signaling. Loss of myelinating oligodendrocytes is a central feature of many neurological diseases, including multiple sclerosis (MS). The results of neuropathological studies suggest that oligodendrocytes react with differing sensitivity to toxic insults, with some cells dying early during lesion development and some cells being resistant for weeks. This proposed graded vulnerability has never been demonstrated but provides an attractive window for therapeutic interventions. Furthermore, the biochemical pathways associated with graded oligodendrocyte vulnerability have not been well explored. We used immunohistochemistry and serial block-face scanning electron microscopy (3D-SEM) to show that cuprizone-induced metabolic stress results in an "out of phase" degeneration of oligodendrocytes. Although expression induction of stress response transcription factors in oligodendrocytes occurs within days, subsequent oligodendrocyte apoptosis continues for weeks. In line with the idea of an out of phase degeneration of oligodendrocytes, detailed ultrastructural reconstructions of the axon-myelin unit demonstrate demyelination of single internodes. In parallel, genome wide array analyses revealed an active unfolded protein response early after initiation of the cuprizone intoxication. In addition to the cytoprotective pathways, the pro-apoptotic transcription factor DNA damage-inducible transcript 3 (DDIT3) was induced early in oligodendrocytes. In advanced lesions, DDIT3 was as well expressed by activated astrocytes. Toxin-induced oligodendrocyte apoptosis, demyelination, microgliosis, astrocytosis, and acute axonal damage were less intense in the Ddit3-null mutants. This study identifies DDIT3 as an important regulator of graded oligodendrocyte vulnerability in a MS animal model. Interference with this stress cascade might offer a promising therapeutic approach for demyelinating disorders.
Databáze: OpenAIRE
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