Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease.
Frances M. Platt,Christopher A. Wassif,Alexandria Colaco,Andrea Dardis,Emyr Lloyd-Evans,Bruno Bembi,Forbes D. Porter +6 more
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TLDR
A surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.Abstract:
Cholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources through the uptake of low-density lipoproteins. Cholesterol biosynthesis is a complex, multienzyme-catalyzed pathway involving a series of sequentially acting enzymes. Inherited defects in genes encoding cholesterol biosynthetic enzymes or other regulators of cholesterol homeostasis result in severe metabolic diseases, many of which are rare in the general population and currently without effective therapy. Historically, these diseases have been viewed as discrete disorders, each with its own genetic cause and distinct pathogenic cascades that lead to its specific clinical features. However, studies have recently shown that three of these diseases have an unanticipated mechanistic convergence. This surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.read more
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Development of gene therapy for Niemann-Pick Type C disease
Michael Hughes,Julie Tordo,Giulia Massaro,J Ng,Paul Gissen,Simon N. Waddington,Frances M. Platt,Ahad A. Rahim +7 more
TL;DR: In this article, the authors developed and evaluated gene therapy for Niemann-Pick Type C (NP-C) in a mouse model using an adeno-associated viral (AAV) vector.
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Comparative proximity biotinylation implicates RAB18 in cholesterol mobilization and biosynthesis
Robert S. Kiss,Chicoine J,Khalil Y,Robert Sladek,Hao Yu Chen,Pisaturo A,Martin C,Dale Jd,Brudenell Ta,Archith Kamath,Emanuele Paci,Peter E. Clayton,Jimi Wills,von Kriegsheim A,Tommy Nilsson,Eamonn Sheridan,Handley Mt +16 more
TL;DR: The data demonstrate that GEF-dependent Rab-interactions are highly amenable to interrogation by proximity biotinylation and may suggest that Micro syndrome is a cholesterol biosynthesis disorder.
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Unearthing the Janus-face cholesterogenesis pathways in cancer
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Dissertation
Lysosomal storage disorders and neurodegenerative disease; related mechanisms of pathogenesis and identification of novel therapeutic targets
TL;DR: The study of models of Huntington’s disease have implicated the Niemann-Pick type C1 protein (NPC1) in the pathogenesis of this disease and identified ways in which this could be therapeutically targeted and new therapeutic targets have been identified by these studies.
References
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TL;DR: Cholesterol complexed to apolipoprotein E-containing lipoproteins may explain the delayed onset of CNS synaptogenesis after glia differentiation and neurobehavioral manifestations of defects in cholesterol or lipoprotein homeostasis.
Journal ArticleDOI
Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1
Stephan Rust,Rosier M,Harald Funke,Real J,Amoura Z,Piette Jc,Deleuze Jf,Brewer Hb,Nicolas Duverger,Patrice Denefle,Gerd Assmann +10 more
TL;DR: Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD).
Journal ArticleDOI
The mechanisms of Hedgehog signalling and its roles in development and disease.
TL;DR: Novel biological insights are revealed into the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins, as well as, in vertebrates, primary cilia.
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Binding and Degradation of Low Density Lipoproteins by Cultured Human Fibroblasts COMPARISON OF CELLS FROM A NORMAL SUBJECT AND FROM A PATIENT WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA
TL;DR: It is raised that a prerequisite for the regulation of cholestero-genesis in cultured fibroblasts is the initial binding of low density lipoproteins to the high affinity surface receptor sites and that a defect in this process represents the primary genetic abnormality in the disorder familial hypercholesterolemia.