Pathogenic inflammation in the CNS of mice carrying human PLP1 mutations.
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.
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Janos
J
Groh
Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, QC, Canada.
Hana C
HC
Friedman
Institute of Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany.
Nadiya
N
Orel
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Chi Wang
CW
Ip
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Stefan
S
Fischer
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Irene
I
Spahn
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Erik
E
Schäffner
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Michaela
M
Hörner
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
David
D
Stadler
Department of Neurology, Multiple Sclerosis and Neuroimmunology, University Hospital Wuerzburg, Wuerzburg, Germany.
Mathias
M
Buttmann
Division of Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany.
Csanad
C
Varallyay
Division of Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany.
László
L
Solymosi
Institute of Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany.
Michael
M
Sendtner
Laboratory of Developmental Biology, Ludmer Research and Training Building, McGill University, Montreal, QC, Canada.
Alan C
AC
Peterson
Department of Neurology, Section of Developmental Neurobiology, University Hospital Wuerzburg, D-97080 Wuerzburg, Germany.
Rudolf
R
Martini
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D018991:Myelin Proteolipid Protein / Q000235:genetics* / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D007155:Immunologic Factors; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; C047516:Plp1 protein, mouse