The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients

Joutel, Anne; Andreux, F.; Gaulis, Swann; Domenga, Valérie; Cécillon, Michaelle; Battail, Nicole; Piga, Nadia; Chapon, Françoise; Godfrain, Catherine; Tournier‐Lasserve, Elisabeth

doi:10.1172/jci8047

Cited by 526 publications

(490 citation statements)

References 20 publications

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“…Investigating normal and mutant Notch3 protein expression, Joutel et al (2000) showed that proteolytic processing and distribution in different cell compartments of the mutant form of the protein in vitro are similar than those described in the normal protein. They also observed that in adult human tissues, Notch3 expression is limited to VSMC, whereas in brain vessels of CADASIL patients the extracellular portion of Notch3 (Notch3ECD) accumulates probably in relationship to decreased clearance of the receptor from the cell surface caused by incorrect oligomerisation of the mutant extracellular domain.…”

Section: Do Cadasil Mutations Lead To Loss Of Receptor Function or Acmentioning

confidence: 99%

“…This syndrome is characterised by a predisposition for stroke caused by diffuse angiopathy: the vascular damage, prevalently affecting small cerebral arteries, is situated in the vascular smooth muscle cells (VSMC), which are the only site of expression of the Notch3 gene in human adults (Joutel et al, 2000). Besides progressive degeneration of the VSMC, the vessels walls of CADASIL patients also show accumulation of a material of unknown composition presenting at electron microscope observation as a granular osmiophilic material (GOM) (Baudrimont et al, 1993).…”

Section: The Effects Of Notch Signallingmentioning

confidence: 99%

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Physiology and pathology of notch signalling system

Bianchi

Dotti

Federico

2005

Journal Cellular Physiology

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Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will sumarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

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Section: Do Cadasil Mutations Lead To Loss Of Receptor Function or Acmentioning

confidence: 99%

Section: The Effects Of Notch Signallingmentioning

confidence: 99%

Physiology and pathology of notch signalling system

Bianchi

Dotti

Federico

2005

Journal Cellular Physiology

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“…81,85 These findings have directed mechanistic studies to a neomorphic effect ( Figure 2B). A toxic gain-of-function mechanism is supported by the stereotyped nature of CADASIL mutations (see above) and by data showing that CADASIL-mutant NOTCH3 ECD aggregates accumulate in the extracellular space of small arteries, arterioles, and capillaries: First, ultrastructural examination of microvessels from CADASIL patients reveals pathognomonic granular osmiophilic material that locates to the vicinity of vascular smooth muscle cells and is NOTCH3-positive on immunogold labeling; 86 Second, NOTCH3 immunostaining of CADASIL microvessels reveals massive immunoreactivity that is specific for this condition; 87 Third, immunoblotting of brain homogenates as well as homogenates from isolated arteries demonstrates accumulation and aggregation of NOTCH3 ECD ; 86,88 And fourth, aggregation and accumulation of mutant NOTCH3 can be recapitulated in vitro using scanning for intensely fluorescent targets, a confocal method allowing the detection of single-protein particles in solution. When the multimerization behavior of NOTCH3-EGF 1-5 a fragment encompassing the mutational hot spot for disease-associated mutations, was analyzed, mutant NOTCH3 showed a much stronger tendency to self-aggregate than the wild-type protein.…”

Section: Cerebral Autosomal Dominant Arteriopathy With Subcortical Inmentioning

confidence: 97%

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Haffner

Malik

Dichgans

2015

J Cereb Blood Flow Metab

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Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

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“…CADASIL is caused by single missense mutations, or more rarely by small deletions, in the Notch3 gene which encodes Notch3 protein, a member of a conserved transmembrane receptor family (Notch signalling) (27). Notch 3 is mainly expressed in VSMC, though it is claimed to be expressed ubiquitously in adult human tissues (28). The pathogenetic mechanism leading to CADASIL is not yet completely understood.…”

Section: Cadasilmentioning

confidence: 99%

Apoptosis, Oxidative Stress and Neurological Disease

et al. 2012

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Apoptosis is a selective cell deletion process which requires the triggering of a specific cell death programme. Two main pathways determining cell death have been identified: the extrinsic or receptor-mediated pathway, activated in response to extracellular pro-apoptotic signals, and the intrinsic pathway, activated by extracellular receptor-independent stimuli or by intracellular insults, such as DNA damage and oxidative stress. All these stress signals are integrated by mitochondria which participate by releasing the main effectors of this process: a family of aspartic-specific proteases known as caspase. Today there is much evidence to suggest that deregulation of apoptosis is a key feature of many neurodegenerative disease. Our group sought cell models for the study of apoptotic pathways and for the evaluation of the role of apoptosis in specific neurodegenerative diseases. We focused on oxidative stress-induced apoptosis and activation of the intrinsic mitochondrial pathway. In our in-vitro model, lymphocytes from patients and control subjects were cultured both in basal conditions and with 2-deoxy-D-ribose (dRib), a reducing sugar which induces apoptosis through oxidative stress. In the last ten years, we evaluated the role of apoptosis in the pathogenesis of several neurodegenerative diseases: Ataxiatelangiectasia,Rett syndrome, Mitochondrial disease, Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Here we report some of our ongoing and recently published articles

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The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients

Cited by 526 publications

References 20 publications

Physiology and pathology of notch signalling system

Physiology and pathology of notch signalling system

Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

Apoptosis, Oxidative Stress and Neurological Disease

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