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Brain Cholesterol Metabolism and Its Defects: Linkage to Neurodegenerative Diseases and Synaptic Dysfunction.

Petrov AM, Kasimov MR, Zefirov AL - Acta Naturae (2016 Jan-Mar)

Bottom Line: Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction.We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes.Changes in cholesterol metabolism in Alzheimer's disease, Parkinson's disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

View Article: PubMed Central - PubMed

Affiliation: Kazan Medical University, Department of Normal Physiology, Butlerova str. 49, Kazan, Russia, 420012.

ABSTRACT
Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the body's total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntington's, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimer's disease, Parkinson's disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

No MeSH data available.


Related in: MedlinePlus

Cholesterol synthesis and oxysterol formation. Cholesterol is produced fromacetyl-coenzyme A in a multistage enzymatic process. There are two pathways forcholesterol synthesis; the Bloch and Kandutsch-Russel pathways. De novosynthesized cholesterol can accumulate as cholesterol esters or bemodified by enzymic or non-enzymic oxidation into oxysterols. A wide array ofoxysterols have been described, each of which may have a specific effect oncellular functions. See text for a detailed explanation.
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Figure 1: Cholesterol synthesis and oxysterol formation. Cholesterol is produced fromacetyl-coenzyme A in a multistage enzymatic process. There are two pathways forcholesterol synthesis; the Bloch and Kandutsch-Russel pathways. De novosynthesized cholesterol can accumulate as cholesterol esters or bemodified by enzymic or non-enzymic oxidation into oxysterols. A wide array ofoxysterols have been described, each of which may have a specific effect oncellular functions. See text for a detailed explanation.

Mentions: De novo cholesterol synthesis begins with the transformationof acetyl-CoA into 3-hydroxyl-3-methylglutaryl- coenzyme A (HMG-CoA) via areaction catalyzed by HMG-CoA -synthetase and then by HMG-CoA reductase intomevalonate. The HMG-CoA reductase-catalyzed formation of mevalonate is anirreversible and rate-limiting step in the cholesterol biosynthesis, targetedby statin drugs. There are two cholesterologenic pathways in the brain(Fig. 1).Neurons mainly contain sterols synthesized via theKandutsch-Russel cholesterol synthetic pathway (7-dehydrocholesterol,lanosterol), and astrocytes contain precursors of the Bloch pathway(desmosterol) [10]. The machinery ofcholesterol synthesis resides in the endoplasmic reticulum (ER). Thecholesterol content in the ER shows greater variations than in plasmamembranes. Indeed, the cholesterol environment in the ER influences the totalcholesterol levels in the cell. One of the key players in cholesterolregulation is SREBP-2 (sterol-regulatory element-binding protein), an inactivetranscription factor anchored to the ER membrane and capable of binding to SCAP(SREBP cleavage-activating protein), which functions as a detector ofcholesterol due to a sterol-sensing domain. During high cholesterolconcentrations, the SREBP-2/SCAP complex is retained in the membranes of the ERby the retention proteins INSIG- 1 and -2 (insulin-induced protein 1 and 2). Insterol- depleted cells, the interaction between the INSIG retention complex andSREBP-2/SCAP is lost, allowing SCAP to escort SREBP-2 to the Golgi compartment.Within this organelle, SCAP releases the N-terminal domain of SREBP-2, whichtranslocates to the nucleus to bind sterol regulatory elements (SRE) in thepromoter regions of over 30 target genes encoding enzymes of cholesterolbiosynthesis (Fig. 2)[1, 10-12].


Brain Cholesterol Metabolism and Its Defects: Linkage to Neurodegenerative Diseases and Synaptic Dysfunction.

Petrov AM, Kasimov MR, Zefirov AL - Acta Naturae (2016 Jan-Mar)

Cholesterol synthesis and oxysterol formation. Cholesterol is produced fromacetyl-coenzyme A in a multistage enzymatic process. There are two pathways forcholesterol synthesis; the Bloch and Kandutsch-Russel pathways. De novosynthesized cholesterol can accumulate as cholesterol esters or bemodified by enzymic or non-enzymic oxidation into oxysterols. A wide array ofoxysterols have been described, each of which may have a specific effect oncellular functions. See text for a detailed explanation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837572&req=5

Figure 1: Cholesterol synthesis and oxysterol formation. Cholesterol is produced fromacetyl-coenzyme A in a multistage enzymatic process. There are two pathways forcholesterol synthesis; the Bloch and Kandutsch-Russel pathways. De novosynthesized cholesterol can accumulate as cholesterol esters or bemodified by enzymic or non-enzymic oxidation into oxysterols. A wide array ofoxysterols have been described, each of which may have a specific effect oncellular functions. See text for a detailed explanation.
Mentions: De novo cholesterol synthesis begins with the transformationof acetyl-CoA into 3-hydroxyl-3-methylglutaryl- coenzyme A (HMG-CoA) via areaction catalyzed by HMG-CoA -synthetase and then by HMG-CoA reductase intomevalonate. The HMG-CoA reductase-catalyzed formation of mevalonate is anirreversible and rate-limiting step in the cholesterol biosynthesis, targetedby statin drugs. There are two cholesterologenic pathways in the brain(Fig. 1).Neurons mainly contain sterols synthesized via theKandutsch-Russel cholesterol synthetic pathway (7-dehydrocholesterol,lanosterol), and astrocytes contain precursors of the Bloch pathway(desmosterol) [10]. The machinery ofcholesterol synthesis resides in the endoplasmic reticulum (ER). Thecholesterol content in the ER shows greater variations than in plasmamembranes. Indeed, the cholesterol environment in the ER influences the totalcholesterol levels in the cell. One of the key players in cholesterolregulation is SREBP-2 (sterol-regulatory element-binding protein), an inactivetranscription factor anchored to the ER membrane and capable of binding to SCAP(SREBP cleavage-activating protein), which functions as a detector ofcholesterol due to a sterol-sensing domain. During high cholesterolconcentrations, the SREBP-2/SCAP complex is retained in the membranes of the ERby the retention proteins INSIG- 1 and -2 (insulin-induced protein 1 and 2). Insterol- depleted cells, the interaction between the INSIG retention complex andSREBP-2/SCAP is lost, allowing SCAP to escort SREBP-2 to the Golgi compartment.Within this organelle, SCAP releases the N-terminal domain of SREBP-2, whichtranslocates to the nucleus to bind sterol regulatory elements (SRE) in thepromoter regions of over 30 target genes encoding enzymes of cholesterolbiosynthesis (Fig. 2)[1, 10-12].

Bottom Line: Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction.We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes.Changes in cholesterol metabolism in Alzheimer's disease, Parkinson's disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

View Article: PubMed Central - PubMed

Affiliation: Kazan Medical University, Department of Normal Physiology, Butlerova str. 49, Kazan, Russia, 420012.

ABSTRACT
Cholesterol is an important constituent of cell membranes and plays a crucial role in the compartmentalization of the plasma membrane and signaling. Brain cholesterol accounts for a large proportion of the body's total cholesterol, existing in two pools: the plasma membranes of neurons and glial cells and the myelin membranes . Cholesterol has been recently shown to be important for synaptic transmission, and a link between cholesterol metabolism defects and neurodegenerative disorders is now recognized. Many neurodegenerative diseases are characterized by impaired cholesterol turnover in the brain. However, at which stage the cholesterol biosynthetic pathway is perturbed and how this contributes to pathogenesis remains unknown. Cognitive deficits and neurodegeneration may be associated with impaired synaptic transduction. Defects in cholesterol biosynthesis can trigger dysfunction of synaptic transmission. In this review, an overview of cholesterol turnover under physiological and pathological conditions is presented (Huntington's, Niemann-Pick type C diseases, Smith-Lemli-Opitz syndrome). We will discuss possible mechanisms by which cholesterol content in the plasma membrane influences synaptic processes. Changes in cholesterol metabolism in Alzheimer's disease, Parkinson's disease, and autistic disorders are beyond the scope of this review and will be summarized in our next paper.

No MeSH data available.


Related in: MedlinePlus