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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

Changes in cholesterol metabolism in Niemann Pick disease type C: the impact onsynaptic transmission. See text for a detailed explanation.
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Figure 5: Changes in cholesterol metabolism in Niemann Pick disease type C: the impact onsynaptic transmission. See text for a detailed explanation.

Mentions: There is clear evidence linking a disordered cholesterol metabolism to brainneurodegeneration. Niemann– Pick type C is a rare autosomal recessivedisorder (affecting 1 in 150,000 newborns) characterized by progressiveneuronal death and reduced life expectancy, hepatolienomegaly, and lungdeficiency. The Niemann–Pick type C disease is accompanied by early lossof Purkinje cells in the cerebellum, leading to ataxia[2]. Mutations in either the NPC1(95% of cases) or the NPC2 (5% of cases) gene render the encoded proteins non-functional(Fig. 5).Defective NPC1 or NPC2 in neurons and glial cells do not allowcholesterol and other lipids (glycolipids, in particular) to exit lateendosomes/ lysosomes and traffic to the plasma membrane and the ER[16]. In NPC1-deficient neurons, cholesterol isdramatically decreased in distal axons but accumulates in soma of neurons. Itis likely that the defects seen in the Niemann–Pick type C disorder arecaused by a reduced cholesterol content in axons: presynaptic nerve terminals,in particular. This is consistent with the evidence indicating an alteredcomposition and organization of synaptic vesicles and recycling endosomes innerve terminals with dysfunctional NPC1 [18].The Niemann–Pick type C disorder is accompanied byan elevated accumulation of oxysterols, such as 3β,5α,6β-cholestantriol and 6-ketosterol, in the brain as a result of oxidative stress[2].


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

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

Changes in cholesterol metabolism in Niemann Pick disease type C: the impact onsynaptic transmission. 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 5: Changes in cholesterol metabolism in Niemann Pick disease type C: the impact onsynaptic transmission. See text for a detailed explanation.
Mentions: There is clear evidence linking a disordered cholesterol metabolism to brainneurodegeneration. Niemann– Pick type C is a rare autosomal recessivedisorder (affecting 1 in 150,000 newborns) characterized by progressiveneuronal death and reduced life expectancy, hepatolienomegaly, and lungdeficiency. The Niemann–Pick type C disease is accompanied by early lossof Purkinje cells in the cerebellum, leading to ataxia[2]. Mutations in either the NPC1(95% of cases) or the NPC2 (5% of cases) gene render the encoded proteins non-functional(Fig. 5).Defective NPC1 or NPC2 in neurons and glial cells do not allowcholesterol and other lipids (glycolipids, in particular) to exit lateendosomes/ lysosomes and traffic to the plasma membrane and the ER[16]. In NPC1-deficient neurons, cholesterol isdramatically decreased in distal axons but accumulates in soma of neurons. Itis likely that the defects seen in the Niemann–Pick type C disorder arecaused by a reduced cholesterol content in axons: presynaptic nerve terminals,in particular. This is consistent with the evidence indicating an alteredcomposition and organization of synaptic vesicles and recycling endosomes innerve terminals with dysfunctional NPC1 [18].The Niemann–Pick type C disorder is accompanied byan elevated accumulation of oxysterols, such as 3β,5α,6β-cholestantriol and 6-ketosterol, in the brain as a result of oxidative stress[2].

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