TY - JOUR
T1 - Higher levels of myelin phospholipids in brains of neuronal α-Synuclein transgenic mice precede myelin loss
AU - Grigoletto, Jessica
AU - Pukaß, Katharina
AU - Gamliel, Ayelet
AU - Davidi, Dana
AU - Katz-Brull, Rachel
AU - Richter-Landsberg, Christiane
AU - Sharon, Ronit
N1 - Funding Information: JG was supported by a fellowship donated by the Louis Sheinman family and Israel Science Foundation (ISF) grant #182/12. CRL was supported by the Deutsche Forschungsgemeinschaft (DFG Ri 384/16-2). RS was a recipient of a fellowship of the Hanse-Wissenschaftskolleg (HWK), Germany.
PY - 2017/5/8
Y1 - 2017/5/8
N2 - α-Synuclein is a protein involved in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We investigated the role of neuronal α-Syn in myelin composition and abnormalities. The phospholipid content of purified myelin was determined by 31P NMR in two mouse lines modeling PD, PrP-A53T α-Syn and Thy-1 wt-α-Syn. Significantly higher levels of phospholipids were detected in myelin purified from brains of these α-Syn transgenic mouse models than in control mice. Nevertheless, myelin ultrastructure appeared intact. To further investigate the effect of α-Syn on myelin abnormalities, we systematically analyzed the striatum, a brain region associated with neurodegeneration in PD. An age and disease-dependent loss of myelin basic protein (MBP) signal was detected by immunohistochemistry in striatal striosomes (patches). The age-dependent loss of MBP signal was associated with lower P25α levels in oligodendrocytes. In addition, we found that α-Syn inhibited oligodendrocyte maturation and the formation of membranous sheets in vitro. Based on these results we concluded that neuronal α-Syn is involved in the regulation and/or maintenance of myelin phospholipid. However, axonal hypomyelination in the PD models is evident only in progressive stages of the disease and associated with α-Syn toxicity.
AB - α-Synuclein is a protein involved in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We investigated the role of neuronal α-Syn in myelin composition and abnormalities. The phospholipid content of purified myelin was determined by 31P NMR in two mouse lines modeling PD, PrP-A53T α-Syn and Thy-1 wt-α-Syn. Significantly higher levels of phospholipids were detected in myelin purified from brains of these α-Syn transgenic mouse models than in control mice. Nevertheless, myelin ultrastructure appeared intact. To further investigate the effect of α-Syn on myelin abnormalities, we systematically analyzed the striatum, a brain region associated with neurodegeneration in PD. An age and disease-dependent loss of myelin basic protein (MBP) signal was detected by immunohistochemistry in striatal striosomes (patches). The age-dependent loss of MBP signal was associated with lower P25α levels in oligodendrocytes. In addition, we found that α-Syn inhibited oligodendrocyte maturation and the formation of membranous sheets in vitro. Based on these results we concluded that neuronal α-Syn is involved in the regulation and/or maintenance of myelin phospholipid. However, axonal hypomyelination in the PD models is evident only in progressive stages of the disease and associated with α-Syn toxicity.
KW - Myelin
KW - Parkinson’s disease
KW - Phospholipids
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=85033802677&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s40478-017-0439-3
DO - https://doi.org/10.1186/s40478-017-0439-3
M3 - Article
C2 - 28482862
SN - 2051-5960
VL - 5
SP - 37
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
ER -