1. Higher levels of myelin phospholipids in brains of neuronal α-Synuclein transgenic mice precede myelin loss.
- Author
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Grigoletto J, Pukaß K, Gamliel A, Davidi D, Katz-Brull R, Richter-Landsberg C, and Sharon R
- Subjects
- Aged, Aged, 80 and over, Aging metabolism, Aging pathology, Alzheimer Disease metabolism, Alzheimer Disease pathology, Amyloid beta-Protein Precursor genetics, Amyloid beta-Protein Precursor metabolism, Animals, Brain pathology, Brain ultrastructure, Cells, Cultured, Disease Models, Animal, Female, Humans, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Myelin Basic Protein metabolism, Myelin Sheath pathology, Myelin Sheath ultrastructure, Neurons pathology, Neurons ultrastructure, Parkinson Disease metabolism, Parkinson Disease pathology, Presenilin-1 genetics, Presenilin-1 metabolism, alpha-Synuclein deficiency, alpha-Synuclein genetics, Brain metabolism, Myelin Sheath metabolism, Neurons metabolism, Phospholipids metabolism, alpha-Synuclein metabolism
- Abstract
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
31 P 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.- Published
- 2017
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