Defects In Cholesterol Metabolism Research Articles

Pyrylium-Based Derivatization for Rapid Labeling and Enhanced Detection of Cholesterol in Mass Spectrometry Imaging.

Cholesterol in the central nervous system has been increasingly found to be closely related to neurodegenerative diseases. Defects in cholesterol metabolism can cause structural and functional disorders of the central nervous system. The detection of abnormal cholesterol is of great significance for the cognition of physiological and pathological states of organisms, and the spatial distribution of cholesterol can also provide more clues for our understanding of the complex mechanism of disease. Here, we developed a novel pyrylium-based derivatization reagent combined with matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to visualize cholesterol in biological tissues. A new class of charged hydroxyl derivatization reagents was designed and synthesized, and finally 1-(carboxymethyl)-2,4,6-trimethylpyridinium (CTMP) was screened for tissue derivatization of cholesterol. Different from the shortcomings of traditional hydroxyl labeling methods such as harsh reaction conditions and long reaction time, in our study, we combined the advantages of CTMP itself and the EDCl/HOBt reaction system to achieve instant labeling of cholesterol on tissues through two-step activation. In addition, we also reported changes in cholesterol content in different stages and different brain regions during disease development in SOD1 mutant mouse model. The cholesterol derivatization method we developed provides an efficient way to explore the distribution and spatial metabolic network of cholesterol in biological tissues.

Activity and Stability of Panx1 Channels in Astrocytes and Neuroblastoma Cells Are Enhanced by Cholesterol Depletion.

Pannexin1 (Panx1) is expressed in both neurons and glia where it forms ATP-permeable channels that are activated under pathological conditions such as epilepsy, migraine, inflammation, and ischemia. Membrane lipid composition affects proper distribution and function of receptors and ion channels, and defects in cholesterol metabolism are associated with neurological diseases. In order to understand the impact of membrane cholesterol on the distribution and function of Panx1 in neural cells, we used fluorescence recovery after photobleaching (FRAP) to evaluate its mobility and electrophysiology and dye uptake to assess channel function. We observed that cholesterol extraction (using methyl-β-cyclodextrin) and inhibition of its synthesis (lovastatin) decreased the lateral diffusion of Panx1 in the plasma membrane. Panx1 channel activity (dye uptake, ATP release and ionic current) was enhanced in cholesterol-depleted Panx1 transfected cells and in wild-type astrocytes compared to non-depleted or Panx1 null cells. Manipulation of cholesterol levels may, therefore, offer a novel strategy by which Panx1 channel activation might modulate various pathological conditions.

Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism.

SummaryInborn errors of cholesterol metabolism occur as a result of mutations in the cholesterol synthesis pathway (CSP). Although mutations in the CSP cause a multiple congenital anomaly syndrome, craniofacial abnormalities are a hallmark phenotype associated with these disorders. Previous studies have established that mutation of the zebrafish hmgcs1 gene (Vu57 allele), which encodes the first enzyme in the CSP, causes defects in craniofacial development and abnormal neural crest cell (NCC) differentiation. However, the molecular mechanisms by which the products of the CSP disrupt NCC differentiation are not completely known. Cholesterol is known to regulate the activity of WNT signaling, an established regulator of NCC differentiation. We hypothesized that defects in cholesterol synthesis are associated with reduced WNT signaling, consequently resulting in abnormal craniofacial development. To test our hypothesis we performed a combination of pharmaceutical inhibition, gene expression assays, and targeted rescue experiments to understand the function of the CSP and WNT signaling during craniofacial development. We demonstrate reduced expression of four canonical WNT downstream target genes in homozygous carriers of the Vu57 allele and reduced axin2 expression, a known WNT target gene, in larvae treated with Ro‐48‐8071, an inhibitor of cholesterol synthesis. Moreover, activation of WNT signaling via treatment with WNT agonist I completely restored the craniofacial defects present in a subset of animals carrying the Vu57 allele. Collectively, these data suggest interplay between the CSP and WNT signaling during craniofacial development.

Immune Cell Intolerance for Excess Cholesterol

Chronic metabolic challenges have severe consequences on physiological systems. In this issue of Immunity, Ito etal. (2016) show that defects in cholesterol metabolism in CD11c+ immune cells result in impaired antigen presentation and ultimately in autoimmune disease.

RAGE Against the ABCs.

Diabetes is an insidious disease that significantly contributes to the development of atherosclerotic cardiovascular disease (CVD). One of the major factors contributing to atherosclerosis is the accumulation of lipid-laden macrophages in the vascular wall (1). Removal of cholesterol from macrophages is essential for the regression of atherosclerotic lesions. This can be achieved by cholesterol-lowering drugs (i.e., statins) or by enhancing the reverse cholesterol transport pathway (i.e., raising HDL). Unfortunately, in the setting of diabetes, cholesterol-lowering drugs such as statins can be less effective (2), and preclinical models have revealed a major defect in lesion regression even when cholesterol levels are normalized (3–5). This suggests that a major defect in cholesterol metabolism occurs in the setting of diabetes. The Hedrick and Oram laboratories originally discovered that diabetes causes a downregulation of the ATP binding cassette transporters ABCG1 (6) and ABCA1 (7) in macrophages, promoting foam cell formation. ABCA1 and ABCG1 provide the dominant pathway of cholesterol removal from a number of cells in the body. Yvan-Charvet et al. (8) made the seminal discovery that codeletion of ABCA1/G1 results in a dramatic increase in atherosclerosis. Extensive research on the antiatherogenic role of these transporters has revealed their importance in removing cholesterol from plaque macrophages (9). However, recent discoveries have shown that ABCA1 and ABCG1 regulate the proliferation of hematopoietic stem and progenitor cells to control the abundance of blood monocytes (10). Along with promoting cholesterol efflux from macrophages, suppressing monocyte levels can directly inhibit the progression of atherosclerotic lesions, promote lesion regression, and provide beneficial outcomes after …

Cholesterol in brain disease: sometimes determinant and frequently implicated.

Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell-cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function.

Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells

SummaryNiemann-Pick type C (NPC) disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs) using transcription activator-like effector nucleases (TALENs). We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease.

Lipid rafts: a signaling platform linking cholesterol metabolism to synaptic deficits in autism spectrum disorders

AUTISM AND CHOLESTEROL METABOLISM Autism spectrum disorders (ASDs) are a group of developmental psychiatric disorders characterized by impaired social interaction and communication, and by restricted, repetitive and stereotyped behaviors and interests (Zoghbi and Bear, 2012; Ebert and Greenberg, 2013; Huguet et al., 2013). Since the features of ASDs usually manifest at the early childhood when sensory experience is modifying the development and balance of excitatory and inhibitory synapses, it has been hypothesized that ASDs may be due to the disruption of experience dependent synaptic development and function, resulting in an imbalance between excitation and inhibition in brain (Auerbach et al., 2011; Zoghbi and Bear, 2012; Delorme et al., 2013; Wang and Doering, 2013). Although genetic causes have been identified in many individuals with ASDs, the details about how those causal genes converge on common pathways to alter synaptic homeostasis in ASDs still need to be investigated. Recently, Buchovecky et al. described disturbances in cholesterol homeostasis in animal model of the ASD Rett syndrome (RTT), giving rise to an exciting prospect that changes in cholesterol metabolism might underlie the development of ASDs (Buchovecky et al., 2013). Cholesterol, an essential cell membrane component, influences the establishment and maintenance of synaptic connection and glial cell development in the nervous system. Balanced cholesterol homeostasis is an important aspect of nervous system function (Mauch et al., 2001; Pfrieger, 2003; Linetti et al., 2010; Pfrieger and Ungerer, 2011; Mathews et al., 2014) (Figure 1A). Perturbed cholesterol homeostasis can affect neural development and synaptogenesis and result in synaptic dysfunction, thus may lead to disorders of nervous system (Simons and Ehehalt, 2002; Linetti et al., 2010; Pani et al., 2010; Karasinska and Hayden, 2011). Evidence from patients indicates that cholesterol homeostasis could be altered in autistic disorders. The Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7), has been found to be associated with autism, supporting genetic defects in cholesterol metabolism can cause autism (Sikora et al., 2006; Bukelis et al., 2007; Diaz-Stransky and Tierney, 2012). Abnormal cholesterol metabolism has also been observed in patients with the ASD Asperger syndrome and other nonsyndromic ASDs, suggesting different abnormalities of cholesterol metabolism may exist in ASDs (Tierney et al., 2006; Dziobek et al., 2007). However, little is known about the mechanisms that mediate the abnormal cholesterol metabolism in these ASD conditions. RTT is caused largely by mutations in the X-linked methyl CpG-binding protein 2 gene (MECP2) (Baker et al., 2013; Lyst et al., 2013; Xu and PozzoMiller, 2013). In Mecp2 mutant mice, Buchovecky et al. found that the expression of genes (Hmgcr, Sqle and Cyp46a1) which encode key enzymes (3-hydroxy-3methylglutaryl-CoA reductase, squalene epoxidase, CYP46A1) in the cholesterol metabolic pathway and cholesterol concentrations are altered in the brain in a development dependent manner (Buchovecky et al., 2013). Their study indicates that loss of Mecp2 disrupts cholesterol homeostasis, suggesting abnormal cholesterol metabolism might be involved in the pathogenesis of RTT (Nagy and Ackerman, 2013). It thus links the autism associated gene to cholesterol metabolism, providing further insights into the relationship between cholesterol metabolism and ASDs.

Development of a Conditional Mesd (Mesoderm Development) Allele for Functional Analysis of the Low-Density Lipoprotein Receptor-Related Family in Defined Tissues

The Low-density lipoprotein receptor-Related Protein (LRP) family members are essential for diverse processes ranging from the regulation of gastrulation to the modulation of lipid homeostasis. Receptors in this family bind and internalize a diverse array of ligands in the extracellular matrix (ECM). As a consequence, LRPs regulate a wide variety of cellular functions including, but not limited to lipid metabolism, membrane composition, cell motility, and cell signaling. Not surprisingly, mutations in single human LRPs are associated with defects in cholesterol metabolism and development of atherosclerosis, abnormalities in bone density, or aberrant eye vasculature, and may be a contributing factor in development of Alzheimer’s disease. Often, members of this diverse family of receptors perform overlapping roles in the same tissues, complicating the analysis of their function through conventional targeted mutagenesis. Here, we describe development of a mouse Mesd (Mesoderm Development) conditional knockout allele, and demonstrate that ubiquitous deletion of Mesd using Cre-recombinase blocks gastrulation, as observed in the traditional knockout and albino-deletion phenotypes. This conditional allele will serve as an excellent tool for future characterization of the cumulative contribution of LRP members in defined tissues.

Abstract 18972: A 36-Year-Old Man with Stroke and Severe Hyperlipidemia: From Phenotype to Genotype

A 36-year-old man with a history of hypertension and hyperlipidemia was admitted to the hospital with headaches, a left visual field deficit and a right occipital lobe infarct. Family history is notable for multiple maternal relatives with premature coronary artery disease and severe hyperlipidemia. Laboratory testing revealed an LDL level of 325 mg/dl. Echocardiography demonstrated a bicuspid aortic valve and two highly mobile thrombi at the sinotubular junction. Because there was no aortic false lumen and the clinical picture was most suspicious for a ruptured aortic root atheroma, we administered intravenous heparin with plans for aortic thrombectomy pending his hemodynamics, neurological status and changes in the echocardiographic apperance of the presumed thrombi. On day three, the patient experienced acute chest pain and ST elevation concerning for abrupt occlusion of the right coronary artery. He was taken emergently to the operating room where two thrombi_one of which was lodged in the right coronary ostium_were removed and aortic endarterectomy was performed. Histology of the aortic specimen showed atherosclerosis and inflammation but no evidence of medial degeneration. The histologic evidence of atherosclerosis focused attention on the patient’s personal and family history of severe hypercholesterolemia. To assess for a genetic defect in cholesterol metabolism, we directly sequenced the LDL receptor gene and identified a heterozygous missense mutation associated with familial hypercholesterolemia (FH). Aortic root disease is common in FH homozygotes, but its presence in a heterozygote suggests an additional inherited or acquired risk factor and prompts further investigation. The bicuspid valve raises the possibility of a subclinical aortic condition that may have contributed to this unusual syndrome. This case directly illustrates the consequences of aortic plaque rupture and emphasizes the multidisciplinary clinical approaches that are central to understanding the complex links between genotype and phenotype even in a well-characterized "simple" monogenic disorder.

Cholesterol: its regulation and role in central nervous system disorders.

Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer's disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules). We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.

Treatment of Smith-Lemli-Opitz syndrome and retina function determined by electroretinography

The purpose of this study was to determine the effect of treatment with cholesterol and antioxidant (AquADEKs) supplementation on retina function in patients with Smith-Lemli-Optiz syndrome (SLOS) by electroretinography. SLOS is an autosomal recessive disease caused by a defect in cholesterol metabolism, resulting in cholesterol deficiency, elevated 7-dehydrocholesterol (7DHC) and progressive retinal dysfunction. Phototransduction is abnormal in SLOS, likely due to high levels of 7DHC in cell membranes of photoreceptors, free radical formation and retinal cell death. Cholesterol and antioxidant supplementation may protect against SLOS retinopathy.

AMP‐activated protein kinase: a potential player in Alzheimer’s disease

AMP-activated protein kinase (AMPK) stimulates energy production via glucose and lipid metabolism, whereas it inhibits energy consuming functions, such as protein and cholesterol synthesis. Increased cytoplasmic AMP and Ca(2+) levels are the major activators of neuronal AMPK signaling. Interestingly, Alzheimer's disease (AD) is associated with several abnormalities in neuronal energy metabolism, for example, decline in glucose uptake, mitochondrial dysfunctions and defects in cholesterol metabolism, and in addition, with problems in maintaining Ca(2+) homeostasis. Epidemiological studies have also revealed that many metabolic and cardiovascular diseases are risk factors for cognitive impairment and sporadic AD. Emerging studies indicate that AMPK signaling can regulate tau protein phosphorylation and amyloidogenesis, the major hallmarks of AD. AMPK is also a potent activator of autophagic degradation which seems to be suppressed in AD. All these observations imply that AMPK is involved in the pathogenesis of AD. However, the responses of AMPK activation are dependent on stimulation and the extent of activating stress. Evidently, AMPK signaling can repress and delay the appearance of AD pathology but later on, with increasing neuronal stress, it can trigger detrimental effects that augment AD pathogenesis. We will outline the potential role of AMPK function in respect to various aspects affecting AD pathogenesis.

Genetic connections between neurological disorders and cholesterol metabolism

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 defined 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.

Fatal adenovirus type 7b infection in a child with Smith‐Lemli‐Opitz syndrome

Adenovirus type 7 causes worldwide respiratory tract infections, mainly in children. Severe systemic infections can occur, especially in immunocompromised patients and in patients with underlying chronic diseases. This report describes the first case of a fatal disseminated adenovirus type 7 infection in a child with Smith-Lemli-Opitz syndrome, a rare autosomal recessive disorder due to a primary enzymatic defect in cholesterol metabolism. Nasopharyngeal secretions and autopsy specimens including liver, lung, pleural fluid, and rectum were collected for viral culture. Adenovirus serotype 7 strains were obtained from all anatomic sites, except the liver. All these clinical isolates were analyzed using restriction endonuclease digestion of the genome, identifying them as genome type 7b, a virulent type. In this case, the fatal evolution could have been accelerated by the presence of an immunodeficiency although immunodeficiency is not included in the definition of Smith-Lemli-Opitz syndrome. The frequent recurrent banal infections in Smith-Lemli-Opitz syndrome could be prevented by a cholesterol supplementation regimen. Finally, this report emphasizes the need for efficient therapy for disseminated adenovirus infections, especially for virulent genome types. J. Med. Virol. 65:66–69, 2001. © 2001 Wiley-Liss, Inc.

Fatal adenovirus type 7b infection in a child with Smith‐Lemli‐Opitz syndrome

Adenovirus type 7 causes worldwide respiratory tract infections, mainly in children. Severe systemic infections can occur, especially in immunocompromised patients and in patients with underlying chronic diseases. This report describes the first case of a fatal disseminated adenovirus type 7 infection in a child with Smith‐Lemli‐Opitz syndrome, a rare autosomal recessive disorder due to a primary enzymatic defect in cholesterol metabolism. Nasopharyngeal secretions and autopsy specimens including liver, lung, pleural fluid, and rectum were collected for viral culture. Adenovirus serotype 7 strains were obtained from all anatomic sites, except the liver. All these clinical isolates were analyzed using restriction endonuclease digestion of the genome, identifying them as genome type 7b, a virulent type. In this case, the fatal evolution could have been accelerated by the presence of an immunodeficiency although immunodeficiency is not included in the definition of Smith‐Lemli‐Opitz syndrome. The frequent recurrent banal infections in Smith‐Lemli‐Opitz syndrome could be prevented by a cholesterol supplementation regimen. Finally, this report emphasizes the need for efficient therapy for disseminated adenovirus infections, especially for virulent genome types. J. Med. Virol. 65:66–69, 2001. © 2001 Wiley‐Liss, Inc.

Inborn errors of metabolism: a cause of abnormal brain development.

Brain malformations are caused by a disruption in the sequence of normal development by various environmental or genetic factors. By modifying the intrauterine milieu, inborn errors of metabolism may cause brain dysgenesis. However, this association is typically described in single case reports. The authors review the relationship between brain dysgenesis and specific inborn errors of metabolism. Peroxisomal disorders and fatty acid oxidation defects can produce migration defects. Pyruvate dehydrogenase deficiency, nonketotic hyperglycinemia, and maternal phenylketonuria preferentially cause a dysgenetic corpus callosum. Abnormal metabolism of folic acid causes neural tube defects, whereas defects in cholesterol metabolism may produce holoprosencephaly. Various mechanisms have been proposed to explain abnormal brain development in inborn errors of metabolism: production of a toxic or energy-deficient intrauterine milieu, modification of the content and function of membranes, or disturbance of the normal expression of intrauterine genes responsible for morphogenesis. The recognition of a metabolic disorder as the cause of the brain malformation has implications for both the care of the patient and for genetic counseling to prevent recurrence in subsequent pregnancies.

Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) is a genetic condition characterized by dysmorphic facies, mental retardation and multiple malformations. A specific defect in cholesterol metabolism, 7-dehydrocholesterol-Δ7 reductase (DHCR7) deficiency due to mutation of theDHCR7gene is the underlying cause of this syndrome. DHCR7 is a microsomal enzyme that catalyzes the conversion of 7-dehydrocholesterol (7DHC) to cholesterol. Hence, affected individuals exhibit low plasma cholesterol and high 7DHC levels. The phenotype most likely results from the combination of cholesterol deficiency and 7DHC accumulation. Diagnosis is based on clinical findings with confirmation by plasma sterol analysis. Prenatal diagnosis may be performed by sterol analysis of amniotic fluid/amniocytes or chorionic villi, or enzyme assay of chorionic villi. Maternal serum estriol and urine sterol analyses provide the opportunity for noninvasive prenatal diagnostic testing. Preliminary evidence from animal and human studies shows that dietary cholesterol supplementation may be beneficial for SLOS patients, but issues including prenatal onset of damage plus poor transport of cholesterol across the blood-brain barrier may limit treatment efficacy. The incidence of SLOS has been estimated to be one in 20,000 to one in 60,000 making it one of the most common autosomal recessive disorders. Recent studies suggest that the carrier frequency is much higher than the disease incidence would suggest.▪ The Endocrinologist 2000; 10: 300-313

Cholesterol Requirement for Neurotrophin Signals

Death from Niemann-Pick type C (NP-C) disease is caused by progressive neurodegeneration. The gene mutated in NP-C is involved the regulation of cholesterol metabolism. Cholesterol is important for the formation of lipid rafts that are postulated to be sites of organization of signaling complexes. Henderson et al . provide evidence for abnormal cholesterol metabolism in cultured neurons from npc nih mice that have a mutation in the NP-C gene that results in a phenotype resembling human NP-C disease. Furthermore, the mutant cells do not respond to the neurotrophin brain-derived neurotrophic factor (BDNF), which stimulates the TrkB receptor in these cells. The mutant cells neither exhibited tyrosine phosphorylation of the TrkB receptor nor responded to BDNF with an increase in neurite outgrowth. The lack of response to BDNF could be mimicked in wild-type cells by depleting the cells of cholesterol, strengthening the idea that cholesterol plays an important role in promoting cell signaling in response to extracellular factors. The data provide a mechanistic link between altered cholesterol metabolism and neurodegeneration. Henderson, L.P., Lin, L., Prasad, A., Paul, C.A., Chang, T.Y., and Maue, R.A. (2000) Embryonic striatal neurons from Niemann-Pick type C mice exhibits defects in cholesterol metabolism and neurotrophin responsiveness. J. Biol. Chem. 275 : 20179-20187. [Abstract] [Full Text]

Embryonic Striatal Neurons from Niemann-Pick Type C Mice Exhibit Defects in Cholesterol Metabolism and Neurotrophin Responsiveness

Niemann-Pick type C (NP-C) disease is a progressive and fatal neuropathological disorder previously characterized by abnormal cholesterol metabolism in peripheral tissues. Although a defective gene has been identified in both humans and the npc(nih) mouse model of NP-C disease, how this leads to abnormal neuronal function is unclear. Here we show that whereas embryonic striatal neurons from npc(nih) mice can take up low density lipoprotein-derived cholesterol, its subsequent hydrolysis and esterification are significantly reduced. Given the importance of cholesterol to a variety of signal transduction mechanisms, we assessed the effect of this abnormality on the ability of these neurons to respond to brain-derived neurotrophic factor (BDNF). In contrast to its effects on wild type neurons, BDNF failed to induce autophosphorylation of the TrkB receptor and to increase neurite outgrowth in npc(nih) neurons, despite expression of TrkB on the cell surface. The results suggest that abnormal cholesterol metabolism occurs in neurons in the brain during NP-C disease, even at embryonic stages of development prior to the onset of phenotypic symptoms. Moreover, this defect is associated with a lack of TrkB function and BDNF responsiveness, which may contribute to the loss of neuronal function observed in NP-C disease.