Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Spooren W, Fuss B, Mallon B, Macklin WB, Fujiwara H, Hasegawa M, Iwatsubo T, Kretzschmar HA, Haass C.
Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes.
EMBO Rep. 2002 Jun;3(6):583-8.
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Alpha-synuclein inclusions are associated with a number of different neurodegenerative diseases that are grouped under the term, synucleinopathies. The type of cell that develops inclusions and the type of cell that degenerates differs among each synucleinopathy. Multiple system atrophy is unusual in that aggregates of alpha-synuclein accumulate (MSA) in oligodendrocytes, which are cells that typically do not express significant amounts alpha-synuclein. This paper is the first paper to specifically model MSA by driving alpha-synuclein expression in oligodendrocytes. The results are striking because there the oligodendrocytes develop inclusions very reminiscent of MSA.
This raises the possibility that simply over-expressing alpha-synuclein in oligodendrocytes is sufficient to drive its aggregation. An important question is whether the mice develop clinical symptoms characteristic of MSA. If so, this will be one of the first transgenic synuclein models truly resembling a synucleinopathies. Previous transgenic mice over-expressing alpha synuclein develop inclusions and clinical symptoms, but the distribution of the inclusions does not resemble that of Parkinson's disease, MSA or diffuse Lewy body disease, although the most recent animal generated by Virginia Lee and John Trojanowsky's group did show neuropathology with ultrastructural features resembling human synucleinopathies. Study of this animal might provide significant insights into MSA.