Targeted overexpression of human alpha-synuclein in oligodendroglia induces lesions linked to MSA-like progressive autonomic failure.
Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause manifesting with progressive autonomic failure (AF), cerebellar ataxia and parkinsonism due to neuronal loss in multiple brain areas associated with (oligodendro)glial cytoplasmic alpha-synuclein (alpha SYN) inclusions (GCIs). Using proteolipid protein (PLP)-alpha-synuclein (alpha SYN) transgenic mice we have previously reported parkinsonian motor deficits triggered by MSA-like alpha SYN inclusions. We now extend these observations by demonstrating degeneration of brain areas that are closely linked to progressive AF and other non-motor symptoms in MSA, in (PLP)-alpha SYN transgenic mice as compared to age-matched non-transgenic controls. We show delayed loss of cholinergic neurons in nucleus ambiguus at 12 months of age as well as early neuronal loss in laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and Onuf's nucleus at 2 months of age associated with alpha SYN oligodendroglial overexpression. We also report that neuronal loss triggered by MSA-like alpha SYN inclusions is absent up to 12 months of age in the thoracic intermediolateral cell column suggesting a differential dynamic modulation of alpha SYN toxicity within the murine autonomic nervous system. Although the spatial and temporal evolution of central autonomic pathology in MSA is unknown our findings corroborate the utility of the (PLP)-alpha SYN transgenic mouse model as a testbed for the study of oligodendroglial alpha SYN mediated neurodegeneration replicating both motor and non-motor aspects of MSA.
Stemberger
Sylvia
S
Division of Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
Poewe
Werner
W
Wenning
Gregor K
GK
Stefanova
Nadia
N
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
D051844:alpha-Synuclein