Effects of the cholesterol-lowering compound methyl-beta-cyclodextrin in models of alpha-synucleinopathy.
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 (MbetaCD), a cholesterol-extracting agent, interfered with alpha-syn accumulation in models of synucleinopathy. For this purpose, we studied the effects of MbetaCD on the accumulation of alpha-syn in a transfected neuronal cell line and in transgenic mice. Immunoblot analysis showed that MbetaCD 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 MbetaCD 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.
Bar-On
Pazit
P
Department of Neurosciences, University of California, San Diego, La Jolla, 92093-0624, USA.
Rockenstein
Edward
E
Adame
Anthony
A
Ho
Gilbert
G
Hashimoto
Makoto
M
Masliah
Eliezer
E
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001923:Brain Chemistry; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002499:Centrifugation, Density Gradient; D002784:Cholesterol / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000517:prevention & control*; D023282:Nuclease Protection Assays; D051844:alpha-Synuclein / Q000378:metabolism / Q000502:physiology*; D047392:beta-Cyclodextrins / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; D002784:Cholesterol