Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases

Schoemaker, Dorothée; Arboleda‐Velásquez, Joseph F.

doi:10.1016/j.ajpath.2021.03.015

Cited by 21 publications

(23 citation statements)

References 101 publications

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“…19 Most studies suggest that CADASIL is caused by toxic effects of the mutant protein, with the GOM in vessel walls being central in its pathophysiology, but the contribution of loss of function effects of NOTCH3 variants is a matter of debate and it is unclear whether decreased NOTCH3 receptor activity also plays a central role. 20 Several disease characteristics of CADASIL are different from those in our patients. The age of onset is much earlier in our patients than in CADASIL, where patients most often present in the fourth decade.…”

Section: Discussioncontrasting

confidence: 68%

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Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants

et al. 2022

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Objective Heterozygous NOTCH3 variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), with patients typically presenting in adulthood. We describe three patients presenting at an early age with a vascular leukoencephalopathy. Genome sequencing revealed bi-allelic variants in the NOTCH3 gene. Methods Clinical records and available MRI and CT scans of three patients from two unrelated families were retrospectively reviewed. Results The patients presented at 9-14 months of age with developmental delay, seizures, or both. The disease course was characterized by cognitive impairment and variably recurrent strokes, migraine attacks, and seizures. MRI findings pointed at a small vessel disease, with extensive cerebral white matter abnormalities, atrophy, lacunes in the basal ganglia, microbleeds and microcalcifications. The anterior temporal lobes were spared. Bi-allelic cysteine-sparing NOTCH3 variants in exons 1, 32 and 33 were found. Interpretation This study indicates that bi-allelic loss-of-function NOTCH3 variants may cause a vascular leukoencephalopathy, distinct from CADASIL.

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Section: Discussioncontrasting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants

et al. 2022

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“…Moreover, extensive WM astrocytopathy with AQP4 redistribution is observed together with loss of VSMCsindicating further NVU involvement in CADASIL [115,118]. The exact underlying mechanism of NOTCH3 dysfunction in CADASIL, however, is still under debate, since some studies using NOTCH3 knockout mice show that GOMs are not necessary to develop the disease [119][120][121]. Therefore, more innovative models are needed to study the pathophysiology.…”

Section: Megalencephalic Leukoencephalopathy With Subcortical Cysts (...mentioning

confidence: 99%

The neurovascular unit in leukodystrophies: towards solving the puzzle

Zarekiani

Pinto

Hol

et al. 2022

Fluids Barriers CNS

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The neurovascular unit (NVU) is a highly organized multicellular system localized in the brain, formed by neuronal, glial (astrocytes, oligodendrocytes, and microglia) and vascular (endothelial cells and pericytes) cells. The blood–brain barrier, a complex and dynamic endothelial cell barrier in the brain microvasculature that separates the blood from the brain parenchyma, is a component of the NVU. In a variety of neurological disorders, including Alzheimer’s disease, multiple sclerosis, and stroke, dysfunctions of the NVU occurs. There is, however, a lack of knowledge regarding the NVU function in leukodystrophies, which are rare monogenic disorders that primarily affect the white matter. Since leukodystrophies are rare diseases, human brain tissue availability is scarce and representative animal models that significantly recapitulate the disease are difficult to develop. The introduction of human induced pluripotent stem cells (hiPSC) now makes it possible to surpass these limitations while maintaining the ability to work in a biologically relevant human context and safeguarding the genetic background of the patient. This review aims to provide further insights into the NVU functioning in leukodystrophies, with a special focus on iPSC-derived models that can be used to dissect neurovascular pathophysiology in these diseases.

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“…A review on this subject that Dr. Dorothee Schoemaker and I wrote addresses these issues in a comprehensive manner. 4 The review also explores if new terminologies that are more encompassing to the diversity of NOTCH 3 mutations recently associated to small blood vessel disease are in order by introducing the notion of NOTCH3-associated small vessel disease. A similar revision may be helpful of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy due to mutations in HTRA1.…”

Section: Q8mentioning

confidence: 99%

Safe and Effective Disease-Modifying Therapies for Small Blood Vessel Disease in the Brain

Arboleda‐Velásquez

2021

The American Journal of Pathology

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Disclosures: J.F.A-V is listed as an inventor in patent applications for biomarkers and treatments addressing cerebral small vessel disease.J.F.A-V is the Special Editor of the Small Blood Vessel Disease in the Brain Theme Issue.This Editorial introduces this month's special Small Blood Vessel Disease in the Brain Theme Issue, a series of reviews on small blood vessel disease in the brain addressing current knowledge, new mechanisms, biomarkers, and therapeutic approaches.

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Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases

Cited by 21 publications

References 101 publications

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants

Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants

The neurovascular unit in leukodystrophies: towards solving the puzzle

Safe and Effective Disease-Modifying Therapies for Small Blood Vessel Disease in the Brain

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