Journal
JOURNAL OF NEUROCHEMISTRY
Volume 98, Issue 4, Pages 1032-1045Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1471-4159.2006.04017.x
Keywords
cholesterol; cyclodextrin; lipid rafts; Parkinson's disease; synuclein; transgenic
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Funding
- NIA NIH HHS [AG05131, AG18440, AG022074] Funding Source: Medline
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The aggregation of alpha-synuclein (alpha-syn) is believed to play a critical role in the pathogenesis of disorders such as dementia with Lewy bodies and Parkinson's disease. The function of alpha-syn remains unclear, although several lines of evidence suggest that alpha-syn is involved in synaptic vesicle trafficking, probably via lipid binding, and interactions with lipids have been shown to regulate alpha-syn aggregation. In this context, the main objective of this study was to determine whether methyl-beta-cyclodextrin (M beta CD), a cholesterol-extracting agent, interfered with alpha-syn accumulation in models of synucleinopathy. For this purpose, we studied the effects of M beta CD on the accumulation of alpha-syn in a transfected neuronal cell line and in transgenic mice. Immunoblot analysis showed that M beta CD reduced the level of alpha-syn in the membrane fraction and detergent-insoluble fraction of transfected cells. In agreement with the in vitro studies, treatment of mice with M beta CD resulted in decreased levels of alpha-syn in membrane fractions and reduced accumulation of alpha-syn in the neuronal cell body and synapses. Taken together, these results suggest that changes in cholesterol and lipid composition using cholesterol-lowering agents may be used as a tool for the treatment of synucleinopathies.
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