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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

Synaptic transmission: lipid-protein interactions. The neurotransmitter isreleased from the synaptic vesicles upon fusion (exocytosis) with thepresynaptic membrane at a specific site (termed active zone) in response toCa2+ influx via potential-gated Ca-channels. The vesicle fusion isgoverned by proteins forming a SNARE complex (synaptobrevin, syntaxin, SNAP-25)and is dictated by numerous cholesterol-binding proteins (synaptotagmin,Munc-18, NCS-1) and signaling molecules (protein kinases, NADPH-oxidase/Nox).After fusion, the protein and lipid components of the vesicles undergoclathrin-mediated endocytosis. The vast majority of synaptic vesicles form thereserve pool, which maintains neurotransmission during prolonged synapticactivity. These vesicles are translocated into the active zone through anactin-and synapsin-dependent pathway. Glutamate released from the synapticvesicles changes the Na+/Ca2+ conductivity of thepostsynaptic membrane by activating AMPA/NMDA receptors. The surface expressionof the postsynaptic receptors is dependent on the exo-and endocytotictrafficking of these receptors, which is regulated by small GTPase (Rab11) andprotein kinase (Cdc42, GSK3β, phosphoinositol-3-kinase/PI-3-K). Thereceptor-dependent signaling is associated with many proteins (Src, ERC,Cav-1). As illustratedin Fig.2.Cholesterol molecules and its clusters are shown in black,phosphoinositol-4,5-biphosphates (PI-4,5-P2,) in red, andcholesterol/PI-4,5-P2-binding proteins. See text for a detailed explanation.
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Figure 3: Synaptic transmission: lipid-protein interactions. The neurotransmitter isreleased from the synaptic vesicles upon fusion (exocytosis) with thepresynaptic membrane at a specific site (termed active zone) in response toCa2+ influx via potential-gated Ca-channels. The vesicle fusion isgoverned by proteins forming a SNARE complex (synaptobrevin, syntaxin, SNAP-25)and is dictated by numerous cholesterol-binding proteins (synaptotagmin,Munc-18, NCS-1) and signaling molecules (protein kinases, NADPH-oxidase/Nox).After fusion, the protein and lipid components of the vesicles undergoclathrin-mediated endocytosis. The vast majority of synaptic vesicles form thereserve pool, which maintains neurotransmission during prolonged synapticactivity. These vesicles are translocated into the active zone through anactin-and synapsin-dependent pathway. Glutamate released from the synapticvesicles changes the Na+/Ca2+ conductivity of thepostsynaptic membrane by activating AMPA/NMDA receptors. The surface expressionof the postsynaptic receptors is dependent on the exo-and endocytotictrafficking of these receptors, which is regulated by small GTPase (Rab11) andprotein kinase (Cdc42, GSK3β, phosphoinositol-3-kinase/PI-3-K). Thereceptor-dependent signaling is associated with many proteins (Src, ERC,Cav-1). As illustratedin Fig.2.Cholesterol molecules and its clusters are shown in black,phosphoinositol-4,5-biphosphates (PI-4,5-P2,) in red, andcholesterol/PI-4,5-P2-binding proteins. See text for a detailed explanation.

Mentions: A schematic representation of signal transduction at the synapse is illustratedin Fig. 3.The presynaptic nerve terminals contain vesiclesfilled with neurotransmitters. In response to the action potential-drivenCa2+ influx, through potential-dependent Ca2+ channels,synaptic vesicles fuse with the presynaptic membrane (exocytosis), allowing theneurotransmitter to diffuse across the synaptic cleft. Following release ontothe postsynaptic membrane, the neurotransmitter activates and alters thepostsynaptic membrane potential. The synaptic transmission is one of the highlyordered cell processes. The efficiency of signal transduction lays the basisfor integrative phenomena and can support the survival and function of neurons[37].


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

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

Synaptic transmission: lipid-protein interactions. The neurotransmitter isreleased from the synaptic vesicles upon fusion (exocytosis) with thepresynaptic membrane at a specific site (termed active zone) in response toCa2+ influx via potential-gated Ca-channels. The vesicle fusion isgoverned by proteins forming a SNARE complex (synaptobrevin, syntaxin, SNAP-25)and is dictated by numerous cholesterol-binding proteins (synaptotagmin,Munc-18, NCS-1) and signaling molecules (protein kinases, NADPH-oxidase/Nox).After fusion, the protein and lipid components of the vesicles undergoclathrin-mediated endocytosis. The vast majority of synaptic vesicles form thereserve pool, which maintains neurotransmission during prolonged synapticactivity. These vesicles are translocated into the active zone through anactin-and synapsin-dependent pathway. Glutamate released from the synapticvesicles changes the Na+/Ca2+ conductivity of thepostsynaptic membrane by activating AMPA/NMDA receptors. The surface expressionof the postsynaptic receptors is dependent on the exo-and endocytotictrafficking of these receptors, which is regulated by small GTPase (Rab11) andprotein kinase (Cdc42, GSK3β, phosphoinositol-3-kinase/PI-3-K). Thereceptor-dependent signaling is associated with many proteins (Src, ERC,Cav-1). As illustratedin Fig.2.Cholesterol molecules and its clusters are shown in black,phosphoinositol-4,5-biphosphates (PI-4,5-P2,) in red, andcholesterol/PI-4,5-P2-binding proteins. 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 3: Synaptic transmission: lipid-protein interactions. The neurotransmitter isreleased from the synaptic vesicles upon fusion (exocytosis) with thepresynaptic membrane at a specific site (termed active zone) in response toCa2+ influx via potential-gated Ca-channels. The vesicle fusion isgoverned by proteins forming a SNARE complex (synaptobrevin, syntaxin, SNAP-25)and is dictated by numerous cholesterol-binding proteins (synaptotagmin,Munc-18, NCS-1) and signaling molecules (protein kinases, NADPH-oxidase/Nox).After fusion, the protein and lipid components of the vesicles undergoclathrin-mediated endocytosis. The vast majority of synaptic vesicles form thereserve pool, which maintains neurotransmission during prolonged synapticactivity. These vesicles are translocated into the active zone through anactin-and synapsin-dependent pathway. Glutamate released from the synapticvesicles changes the Na+/Ca2+ conductivity of thepostsynaptic membrane by activating AMPA/NMDA receptors. The surface expressionof the postsynaptic receptors is dependent on the exo-and endocytotictrafficking of these receptors, which is regulated by small GTPase (Rab11) andprotein kinase (Cdc42, GSK3β, phosphoinositol-3-kinase/PI-3-K). Thereceptor-dependent signaling is associated with many proteins (Src, ERC,Cav-1). As illustratedin Fig.2.Cholesterol molecules and its clusters are shown in black,phosphoinositol-4,5-biphosphates (PI-4,5-P2,) in red, andcholesterol/PI-4,5-P2-binding proteins. See text for a detailed explanation.
Mentions: A schematic representation of signal transduction at the synapse is illustratedin Fig. 3.The presynaptic nerve terminals contain vesiclesfilled with neurotransmitters. In response to the action potential-drivenCa2+ influx, through potential-dependent Ca2+ channels,synaptic vesicles fuse with the presynaptic membrane (exocytosis), allowing theneurotransmitter to diffuse across the synaptic cleft. Following release ontothe postsynaptic membrane, the neurotransmitter activates and alters thepostsynaptic membrane potential. The synaptic transmission is one of the highlyordered cell processes. The efficiency of signal transduction lays the basisfor integrative phenomena and can support the survival and function of neurons[37].

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