Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration.
Transgenic (Tg) mice overexpressing human wild-type alpha-synuclein in oligodendrocytes under the control of the 2,' 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter are shown here to recapitulate features of multiple system atrophy (MSA), including the accumulation of filamentous human alpha-synuclein aggregates in oligodendrocytes linked to their degeneration and autophagocytosis of myelin. Significantly, endogenous mouse alpha-synuclein also accumulated in normal and degenerating axons and axon terminals in association with oligodendroglia and neuron loss and slowly progressive motor impairments. Our studies demonstrate that overexpression of alpha-synuclein in oligodendrocytes of mice results in MSA-like degeneration in the CNS and that alpha-synuclein inclusions in oligodendrocytes participate in the degeneration of neurons in MSA.
Yazawa
Ikuru
I
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Giasson
Benoit I
BI
Sasaki
Ryogen
R
Zhang
Bin
B
Joyce
Sonali
S
Uryu
Kunihiro
K
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D019578:Multiple System Atrophy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010587:Phagocytosis / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000235:genetics; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics; D051843:Synucleins; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D010727:Phosphoric Diester Hydrolases; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571337:CNP protein, human; C571338:Cnp protein, mouse