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p25α relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy

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  • Yun Ju C. Song, Neuroscience Research Australia
  • ,
  • Ditte M.S. Lundvig
  • ,
  • Yue Huang, Neuroscience Research Australia
  • ,
  • Ping Gai Wei, Flinders University
  • ,
  • Peter C. Blumbergs, Flinders University
  • ,
  • Peter Højrup, Syddansk Universitet
  • ,
  • Daniel Otzen
  • Glenda M. Halliday, Neuroscience Research Australia
  • ,
  • Poul H. Jensen
  • Institut for Medicinsk Biokemi
  • Feriefonden ved Aarhus Universitet

p25α is an oligodendroglial protein that can induce aggregation of α-synuclein and accumulates in oligodendroglial cell bodies containing fibrillized α-synuclein in the neurodegenerative disease multiple system atrophy (MSA). We demonstrate biochemically that p25α is a constituent of myelin and a high-affinity ligand for myelin basic protein (MBP), and in situ immunohistochemistry revealed that MBP and p25α colocalize in myelin in normal human brains. Analysis of MSA cases reveals dramatic changes in p25α and MBP throughout the course of the disease. In situ immunohistochemistry revealed a cellular redistribution of p25α immunoreactivity from the myelin to the oligodendroglial cell soma, with no overall change in p25α protein concentration using immunoblotting. Concomitantly, an ∼80% reduction in the concentration of full-length MBP protein was revealed by immunoblotting along with the presence of immunoreactivity for MBP degradation products in oligodendroglia. The oligodendroglial cell bodies in MSA displayed an enlargement along with the relocalization of p25α, and this was enhanced after the deposition of α-synuclein in the glial cytoplasmic inclusions. Overall, the data indicate that changes in the cellular interactions between MBP and p25α occur early in MSA and contribute to abnormalities in myelin and subsequent α-synuclein aggregation and the ensuing neuronal degeneration that characterizes this disease.

TidsskriftAmerican Journal of Pathology
Sider (fra-til)1291-1303
Antal sider13
StatusUdgivet - okt. 2007

Bibliografisk note

Funding Information:
Supported by the National Health and Medical Research Council of Australia (project grant no. 222727 to G.M.H. ); the Danish Research Council for Health and disease (grant 271-05-0166 to P.H.J. ); The Lundbeck Foundation (to P.H.J.); The Nordic Centre of Excellence in Molecular Neurodegenerative Diseases (to P.H.J.); The Danish Parkinson's Disease Foundation (to P.H.J.); the Commonwealth Government of Australia (Ph.D. stipend to Y.J.C.S.); Aarhus University (Ph.D. stipend from the Medical Faculty to D.M.S.L.); the Danish National Research Foundation (inSPIN) (to D.E.O.); the Villum Kann Rasmussen Foundation (bioNET) (to D.E.O.); and the National Health and Medical Research Council of Australia and Neurosciences Australia, Australian Brain Donor Programs (human brain tissue samples were received from the South Australian Brain Bank and the Australian Brain Donor Programs at the Prince of Wales Medical Research Institute Tissue Resource Centre, which are supported by the approved request GH060505 to G.M.H. ).

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