Selective expression of <i>LDLR</i> and <i>VLDLR</i> in myelinating oligodendrocytes

Zhao, Shufang; Hu, Xuemei; Park, Jin‐Sil; Zhu, Ying; Zhu, Qiang; Li, Hong; Luo, Chuping; Han, Rong; Cooper, Nigel G. F.; Qiu, Mengsheng

doi:10.1002/dvdy.21283

Cited by 30 publications

(31 citation statements)

References 27 publications

(37 reference statements)

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“…This indicates that these cells have the capacity to take up lipids from the extracellular environment. Accordingly, transcription analysis in rodents showed that lipoprotein receptors are expressed by oligodendrocytes ( 127 ) and that expression of the low density lipoprotein receptor (LDLR) gene in the PNS is elevated with myelination ( 24 ) although the LDLR gene was found not to be required for PNS remyelination ( 128 ). Which lipoprotein receptors are involved in the uptake of lipids and exactly where on the glial cell they can be found to support membrane growth ( Fig.…”

Section: Why Are Myelinating Glial Cells Particularly Vulnerable To Lmentioning

confidence: 99%

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Chrast

Saher

Nave

et al. 2011

Journal of Lipid Research

244

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Section: Why Are Myelinating Glial Cells Particularly Vulnerable To Lmentioning

confidence: 99%

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Chrast

Saher

Nave

et al. 2011

Journal of Lipid Research

244

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“…Functional analysis of ApoER2 and VLDLR demonstrated a partial redundancy and that the knock-out of both receptors resulted in disorganization of the layers in brain cortex and cerebellum (38). Postnatally VLDLR is expressed in the cerebellar Purkinje cell layer and the underlying granular layer (39). On dry film, comparative ISH analysis of PCSK9 and either ApoER2 or VLDLR mRNAs in a whole mouse at P1 revealed that PCSK9 expression may localize close to that of VLDLR only in cerebellum and possibly with both receptors in kidney cortex (Fig.…”

Section: Membrane-bound Pcsk9 Chimeras Are More Effective In Enhancinmentioning

confidence: 99%

The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest Family Members VLDLR and ApoER2

Poirier

Mayer

Benjannet

et al. 2008

Journal of Biological Chemistry

417

337

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The proprotein convertase PCSK9 gene is the third locus implicated in familial hypercholesterolemia, emphasizing its role in cardiovascular diseases. Loss of function mutations and gene disruption of PCSK9 resulted in a higher clearance of plasma low density lipoprotein cholesterol, likely due to a reduced degradation of the liver low density lipoprotein receptor (LDLR). In this study, we show that two of the closest family members to LDLR are also PCSK9 targets. These include the very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) implicated in neuronal development and lipid metabolism. Our results show that wild type PCSK9 and more so its natural gain of function mutant D374Y can efficiently degrade the LDLR, VLDLR, and ApoER2 either following cellular co-expression or re-internalization of secreted human PCSK9. Such PCSK9-induced degradation does not require its catalytic activity. Membrane-bound PCSK9 chimeras enhanced the intracellular targeting of PCSK9 to late endosomes/lysosomes and resulted in a much more efficient degradation of the three receptors. We also demonstrate that the activity of PCSK9 and its binding affinity on VLDLR and ApoER2 does not depend on the presence of LDLR. Finally, in situ hybridization show close localization of PCSK9 mRNA expression to that of VLDLR in mouse postnatal day 1 cerebellum. Thus, this study demonstrates a more general effect of PCSK9 on the degradation of the LDLR family that emphasizes its major role in cholesterol and lipid homeostasis as well as brain development.Familial hypercholesterolemia is mainly characterized by elevated plasma LDL 2 cholesterol that is highly correlated with cardiovascular diseases (1). The main player in regulating the circulating cholesterol is the low density lipoprotein receptor (LDLR), which is expressed mostly in the liver. Recently, natural mutations in the proprotein convertase PCSK9 (2, 3) have been identified and associated with the third locus implicated in familial hypercholesterolemia (4 -6). The major function of PCSK9 seems to be an enhancement of the degradation of the LDLR (7, 8) in acidic subcellular compartments (3), likely endosomes/lysosomes (9, 10). This can occur either via an extracellular endocytotic route (11), or possibly by a direct cellular circuit not involving cell surface endocytosis of the LDLR (12). The gain of function PCSK9 mutations D374Y (13, 14) or D374H (15) have the highest impact on the development of hypercholesterolemia (16), likely through enhanced binding (17) and degradation of the LDLR (18, 19). The major binding site of LDLR to PCSK9 seems to reside within its first epidermal growth factor-like repeat namely EGF-A (20). Finally, it was recently suggested that the PCSK9-induced degradation of the cell surface LDLR does not require its proteolytic activity (21). One of the unanswered questions is the target specificity of PCSK9, and it is not known, nor obvious, whether other members of the LDLR family are also affected by PCSK9. This family consists of str...

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“…Intriguingly, IDOL not only promotes the ubiquitylation of the LDLR (Zelcer et al, 2009) but also two related receptors, the ApoE receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR) (Hong et al, 2010), known to be expressed in oligodendrocytes (Zhao et al, 2007). Indeed, a potential explanation for the rescue of Olig2 levels by Idol depletion in Ndrg1 k/d cells is that uptake of LDL, or other ligands of IDOLregulated receptors, is required to maintain Olig2 expression and oligodendrocyte differentiation.…”

Section: Ndrg1 and Cmt4dmentioning

confidence: 99%

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

Pietiäinen

Vassilev

Blom

et al. 2013

Journal of Cell Science

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Summary N-myc downstream-regulated gene 1 (NDRG1) mutations cause Charcot-Marie-Tooth disease type 4D (CMT4D). However, the cellular function of NDRG1 and how it causes CMT4D are poorly understood. We report that NDRG1 silencing in epithelial cells results in decreased uptake of low-density lipoprotein (LDL) due to reduced LDL receptor (LDLR) abundance at the plasma membrane. This is accompanied by the accumulation of LDLR in enlarged EEA1-positive endosomes that contain numerous intraluminal vesicles and sequester ceramide. Concomitantly, LDLR ubiquitylation is increased but its degradation is reduced and ESCRT (endosomal sorting complex required for transport) proteins are downregulated. Co-depletion of IDOL (inducible degrader of the LDLR), which ubiquitylates the LDLR and promotes its degradation, rescues plasma membrane LDLR levels and LDL uptake. In murine oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also in downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake through LDLR family members controls oligodendrocyte differentiation. These findings identify NDRG1 as a novel regulator of multivesicular body formation and endosomal LDLR trafficking. The deficiency of functional NDRG1 in CMT4D might impair lipid processing and differentiation of myelinating cells.

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Selective expression of LDLR and VLDLR in myelinating oligodendrocytes

Cited by 30 publications

References 27 publications

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models

The Proprotein Convertase PCSK9 Induces the Degradation of Low Density Lipoprotein Receptor (LDLR) and Its Closest Family Members VLDLR and ApoER2

NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation

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