This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Alpha-synuclein is a 140 amino acid protein that is very abundant in the mammalian brain. Its overexpression and mutations in its gene are associated with familial Parkinson's disease. In addition, alpha-synuclein containing aggregates are also hallmarks of other neurological disorders, including the sporadic form of Parkinson's disease, Alzheimer's disease, Lewy body disease, Down's syndrome, and multiple-system atrophy, many of which are also associated with profound alterations in brain cholesterol homeostasis. Despite the association of alpha-synuclein with so many neurological disorders, its physiological function remains poorly described. We have recently demonstrated that alpha-synuclein expression impacts brain cholesterol and cholesteryl ester levels, however the mechanism(s) by which alpha-synuclein influences brain cholesterol and cholesteryl ester metabolism is unknown. In addition, we have observed an increase in astrocyte cholesterol and cholesteryl ester formation. This is especially important because astrocytes are the major site of cholesterol synthesis in the adult brain. Hence, this new link between alpha-synuclein and brain cholesterol metabolism is a critical observation because of the known association between brain cholesterol and neurodegenerative diseases. Understanding the mechanisms underlying this new link will provide significant, new insight into the pathophysiology of alpha-synuclein associated neurological disorders. Based upon our published work, our central hypothesis is that alpha-synuclein facilitates brain cholesterol metabolism by stimulating astrocyte cholesterol efflux and that in the absence of alpha-synuclein, cholesterol is trapped in the astrocyte leading to elevated brain cholesterol levels that are then stored as cholesteryl esters. This central hypothesis will be tested by the following specific aim: Determine the extent to which alpha-synuclein(snca) modulates brain cholesterol metabolism.
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