Genetic connections between neurological disorders and cholesterol metabolism

Abstract

and store such a large amount of cholesterol indicates that there is a close link between the evolution of the nervous system and a specifi c role for cholesterol. Within the brain, some 70% of cholesterol is present in myelin, where it fulfi lls a critical insulating role. It is likely that the requirement for effi cient signaling despite a small transverse diameter of axons was a key selective pressure driving the accretion of cholesterol in the mammalian brain ( 1, 2 ). The requirement for large amounts of cholesterol is further underscored by the long half-life of brain cholesterol; overall brain cholesterol turns over some 250-300 times slower than that in the circulation ( 3 ).At a cellular level, the myelin sheath consists of sections of plasma membrane repeatedly wrapped around an axon, with the extrusion of virtually all of the cytoplasm. Myelin is formed by 2 very specialized cells: the oligodendrocyte in the central nervous system (CNS) and the Schwann cell in the peripheral nervous system (PNS). Because an individual axon may be ensheathed by myelin from several oligodendrocytes, periodic gaps are present in the sheath. These are called the "nodes of Ranvier" and are the site of propagation of the action potential. Myelin can thus be regarded as a discontinuous insulation that enables the saltatory conduction of the action potential ( 1, 2 ). In addition Abstract Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defi ned defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders. -Björkhem, I., V. Leoni, and S. Meaney. The mammalian nervous system contains a disproportionate amount of cholesterol. In the brain, the cholesterol content is about 10-fold greater than in any other organ ( 1 ). The development of the capacity to synthesize

Reply to Valenza and Cattaneo: SIRT2-mediated neuroprotection and cholesterol dyshomeostasis in Huntington’s disease

“…Moreover, the literature shows that abnormal increases, extreme decreases, and even more subtle redistributions of sterols in brain cells can cause or exacerbate neurodegeneration (6). We, therefore, believe that the data by Valenza and Cattaneo (2), as well as our data (1), provide a compelling case for better understanding brain sterol homeostasis and further exploring the impact of HD on this process.…”

Side Chain-oxidized Oxysterols Regulate the Brain Renin-Angiotensin System through a Liver X Receptor-dependent Mechanism

“…Disturbances in cholesterol metabolism and hypercholesterolemia may also play a role in neuropathological conditions (8). The slow conversion of brain cholesterol into the oxysterol 24S-hydroxycholesterol (24S-OH) maintains the homeostasis of cholesterol in the central nervous system (CNS).…”

Relationship Between Cholesterol Metabolism, Apoe and Brain Volumes In Alzheimer‘s Disease

“…Subjects with one or two copies of APOE e4 have a higher risk of developing AD compared with carriers of other isoforms. APOE also reduces the age of AD onset from 84 years (median) in noncarriers to 68 years in APOE e4 homozygotes [12,[26][27][28].…”

“…ApoE isolated from CSF is present in both discoidal and spherical lipoprotein complexes. Before reaching the CSF, some of these particles accumulate cholesterol and form spherical lipoproteins upon esterification of free cholesterol [12,[26][27][28].…”