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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

Alterations in cholesterol synthesis associated with the Smith- Lemli-Opitzsyndrome: an implication in synaptic dysfunction. See text for a detailedexplanation.
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Figure 4: Alterations in cholesterol synthesis associated with the Smith- Lemli-Opitzsyndrome: an implication in synaptic dysfunction. See text for a detailedexplanation.

Mentions: For some diseases, cholesterol metabolism abnormalities are the major cause ofneurodegenerative disorders and birth defects. Lathosterolosis is a retardationsyndrome due to a deficiency in 3β-hydroxysteroid-5- desaturase, anddesmosterolosis is caused by mutations in the3β-hydroxysterol-24-reductase gene. Defective cholesterol-27-hydroxylaseleads to cerebrotendinous xanthomatosis. The Smith-Lemli-Opitz syndrome is themost common autosomal recessive disease of this type (affects 1 in 20,000newborns) resulting from mutations in the dhcr7 gene encoding7-dehydrocholesterolreductase (Dhcr7) [70].Severe forms are deleterious for fetal development andnewborn infant. Dhcr7 catalyzes the final step in the Kandutsch–Russellcholesterol biosynthetic pathway. A consequence of defective Dhcr7 is theaccumulation of 7-dehydrocholesterol (7DHC) in the brain, non-neuronal tissuesand plasma, and ultimately, cholesterol loss(Fig. 4). In theSmith- Lemli-Opitz syndrome, 24-HC levels drop and 27-HC levels increase in theplasma [71]. This disease involvesprofound brain development abnormalities, intellectual disability, as well asemotional and sleep disorders. Patients with severe cases display plasmacholesterol concentrations amounting to 2% of the normal range. In the mildform, plasma cholesterol levels may remain unaffected but that cannot stopbrain developmental defects, pointing to a role for brain cholesterol in thegenesis of neurological symptoms [70].On the other hand, these symptoms could result from the accumulation of theDhcr7 substrate 7,8-dehydrodesmosterol and its oxidized derivatives[72]. The teratogenic activity in theSmith-Lemli-Opitz syndrome seems to be attributed to a deficiency inSHH-signaling, since SHH activity (Sonic Hedgehog morphogen) requires acovalent linkage of cholesterol to SHH [70].


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

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

Alterations in cholesterol synthesis associated with the Smith- Lemli-Opitzsyndrome: an implication in synaptic dysfunction. See text for a detailedexplanation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Alterations in cholesterol synthesis associated with the Smith- Lemli-Opitzsyndrome: an implication in synaptic dysfunction. See text for a detailedexplanation.
Mentions: For some diseases, cholesterol metabolism abnormalities are the major cause ofneurodegenerative disorders and birth defects. Lathosterolosis is a retardationsyndrome due to a deficiency in 3β-hydroxysteroid-5- desaturase, anddesmosterolosis is caused by mutations in the3β-hydroxysterol-24-reductase gene. Defective cholesterol-27-hydroxylaseleads to cerebrotendinous xanthomatosis. The Smith-Lemli-Opitz syndrome is themost common autosomal recessive disease of this type (affects 1 in 20,000newborns) resulting from mutations in the dhcr7 gene encoding7-dehydrocholesterolreductase (Dhcr7) [70].Severe forms are deleterious for fetal development andnewborn infant. Dhcr7 catalyzes the final step in the Kandutsch–Russellcholesterol biosynthetic pathway. A consequence of defective Dhcr7 is theaccumulation of 7-dehydrocholesterol (7DHC) in the brain, non-neuronal tissuesand plasma, and ultimately, cholesterol loss(Fig. 4). In theSmith- Lemli-Opitz syndrome, 24-HC levels drop and 27-HC levels increase in theplasma [71]. This disease involvesprofound brain development abnormalities, intellectual disability, as well asemotional and sleep disorders. Patients with severe cases display plasmacholesterol concentrations amounting to 2% of the normal range. In the mildform, plasma cholesterol levels may remain unaffected but that cannot stopbrain developmental defects, pointing to a role for brain cholesterol in thegenesis of neurological symptoms [70].On the other hand, these symptoms could result from the accumulation of theDhcr7 substrate 7,8-dehydrodesmosterol and its oxidized derivatives[72]. The teratogenic activity in theSmith-Lemli-Opitz syndrome seems to be attributed to a deficiency inSHH-signaling, since SHH activity (Sonic Hedgehog morphogen) requires acovalent linkage of cholesterol to SHH [70].

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