Pathogenic inflammation in the CNS of mice carrying human PLP1 mutations.

Autor:	Groh J; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany., Friedman HC; Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, QC, Canada., Orel N; Institute of Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany., Ip CW; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany., Fischer S; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany., Spahn I; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany., Schäffner E; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany., Hörner M; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany., Stadler D; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany., Buttmann M; Department of Neurology, Multiple Sclerosis and Neuroimmunology, University Hospital Wuerzburg, Wuerzburg, Germany., Varallyay C; Division of Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany., Solymosi L; Division of Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany., Sendtner M; Institute of Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany., Peterson AC; Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, QC, Canada., Martini R; Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2016 Nov 01; Vol. 25 (21), pp. 4686-4702.
DOI:	10.1093/hmg/ddw296
Abstrakt:	Progressive forms of multiple sclerosis lead to chronic disability, substantial decline in quality of life and reduced longevity. It is often suggested that they occur independently of inflammation. Here we investigated the disease progression in mouse models carrying PLP1 point mutations previously found in patients displaying clinical features of multiple sclerosis. These mouse models show loss-of-function of PLP1 associated with neuroinflammation; the latter leading to clinically relevant axonal degeneration, neuronal loss and brain atrophy as demonstrated by inactivation of the recombination activating gene 1. Moreover, these pathological hallmarks were substantially amplified when we attenuated immune regulation by inactivation of the programmed cell death-1 gene. Our observations support the view that primary oligodendroglial abnormalities can evoke pathogenically relevant neuroinflammation that drives neurodegeneration, as observed in some forms of multiple sclerosis but also in other, genetically-mediated neurodegenerative disorders of the human nervous system. As many potent immunomodulatory drugs have emerged during the last years, it is tempting to consider immunomodulation as a treatment option not only for multiple sclerosis, but also for so far non-treatable, genetically-mediated disorders of the nervous system accompanied by pathogenic neuroinflammation.
Databáze:	MEDLINE
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