Part of the book: Atherogenesis
Part of the book: Lipid Metabolism
Previous studies have shown that TSPO as well as apolipoprotein E (Apo E) can be associated with processes such as cholesterol metabolism, oxidative stress, apoptosis, glial activation, inflammation, and immune responses. As a ligand for cell-surface lipoprotein receptors, apolipoprotein E can prevent atherosclerosis by clearing cholesterol-rich lipoproteins from plasma. Furthermore, TSPO takes part in the regulation of gene expression for proteins involved in adhesion, which potentially may play a role in platelet aggregation. There are indications that the Apo E protein is involve in platelet aggregation, while TSPO platelet levels have been found to be increased with various neurological disorders, in particular, in stress-related disorders. The role of platelets in atherogenesis and the potential therapeutic impact of TSPO ligands on disease prevention are of great interest. To determine TSPO binding characteristics in this paradigm, we applied binding assays with [3H]PK 11195 on isolated platelets and erythrocyte membranes. The in vivo findings in Apo E knockout mice revealed that TSPO levels appear to be enhanced in platelets and erythrocytes of Apo E knockout mice, and thus suggest that TSPO and Apo E expression may be interconnected in relation to some aspect of the host defense response. Other organs tested, such as liver, testis, brain, heart, aorta, lung, kidney and spleen, did not show a difference in TSPO binding levels between Apo E knockout mice and wild-type mice. This suggests that TSPO levels may be part of a feedback control system for steroid production (responding to alterations in steroid levels), rather than being regulated by a feed-forward signal provided by cholesterol (i.e. TSPO levels in relation to steroidogenesis are not being regulated by cholesterol levels in vivo).
Part of the book: Thrombosis, Atherosclerosis and Atherothrombosis
The molecular responses to counteract diseases, including insulting conditions such as injury and pathogen infection, involve coordinated modulation of gene expression programs. The association of alpha synuclein (α-Syn) with several progressive disorders has focused the research on its induced conformational behavior as critical for uncovering the “secrets” for progression of α-synucleinopathies. Cholesterol is one of the lipid components crucial for regular proliferation of the nervous tissue. Its interaction with α-Syn may offer other insights to α-Syn normal expression. Discovering that the molecular regulatory mechanisms responsible for prevention of α-Syn aggregation may be manifested through microRNA (miRNA) regulated gene expression is also crucial for widening the perception of neuropathology. The 18-kDa translocator protein (TSPO) localized on the outer mitochondrial membrane is able to regulate various cellular and tissue functions, with key role as cholesterol transporter for neurosteroid synthesis. TSPO up-regulation, has been connected to several diseases, including cancer, neuronal damage, and inflammation. Connection may also be established between TSPO expression and fatty acid oxidation, thus unveiling new possibilities in the research of α-Syn overexpression. However, expression of TSPO in the neuroinflammatory environment is probably the best starting point for targeting TSPO as a suitable therapeutic target.
Part of the book: Synucleins