Cysteine-Sparing CADASIL Mutations in
            <i>NOTCH3</i>
            Show Proaggregatory Properties In Vitro

Wollenweber, Frank Arne; Hanecker, Patrizia; Bayer-Karpinska, Anna; Malik, Rainer; Bäzner, Hansjörg; Moreton, Fiona; Muir, Keith W.; Müller, Susanna; Giese, Armin; Opherk, Christian; Dichgans, Martin; Haffner, Christof; Duering, Marco

doi:10.1161/strokeaha.114.007472

Cited by 44 publications

(46 citation statements)

References 37 publications

(35 reference statements)

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“…NOTCH3 contains a highly conserved even number of cysteines forming disulfide bridges that maintain structural integrity. Any unpaired cysteine stimulates multimerization and aggregation through the loss of a structural disulfides and exposure of an oxidation-prone cysteine that can form non-native disulfide [85,86]. Aggregated NOTCH3 accumulates in the vascular wall, leading to the rare systemic vasculopathology CASADIL.…”

Section: Cysteine Oxidation-driven Protein Aggregation In Diseasementioning

confidence: 99%

Cross-talk between redox signalling and protein aggregation

Dam

Dansen

2020

Biochemical Society Transactions

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It is well established that both an increase in reactive oxygen species (ROS: i.e. O2•−, H2O2 and OH•), as well as protein aggregation, accompany ageing and proteinopathies such as Parkinson's and Alzheimer's disease. However, it is far from clear whether there is a causal relation between the two. This review describes how protein aggregation can be affected both by redox signalling (downstream of H2O2), as well as by ROS-induced damage, and aims to give an overview of the current knowledge of how redox signalling affects protein aggregation and vice versa. Redox signalling has been shown to play roles in almost every step of protein aggregation and amyloid formation, from aggregation initiation to the rapid oligomerization of large amyloids, which tend to be less toxic than oligomeric prefibrillar aggregates. We explore the hypothesis that age-associated elevated ROS production could be part of a redox signalling-dependent-stress response in an attempt to curb protein aggregation and minimize toxicity.

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Section: Cysteine Oxidation-driven Protein Aggregation In Diseasementioning

confidence: 99%

Cross-talk between redox signalling and protein aggregation

Dam

Dansen

2020

Biochemical Society Transactions

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“…Although in silico mutation prediction tools predicted these mutations to be probably pathogenic, functional studies are needed to confirm this pathogenicity. Other non-cysteine affecting NOTCH3 mutations have been described in SVD, although their pathogenicity has been debated [ 25 – 27 ].…”

Section: Discussionmentioning

confidence: 99%

Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke

et al. 2015

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Background and PurposeCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in the NOTCH3 gene, is the most common monogenic disorder causing lacunar stroke and cerebral small vessel disease (SVD). Fabry disease (FD) due to mutations in the GLA gene has been suggested as an underdiagnosed cause of stroke, and one feature is SVD. Previous studies reported varying prevalence of CADASIL and FD in stroke, likely due to varying subtypes studied; no studies have looked at a large cohort of younger onset SVD. We determined the prevalence in a well-defined, MRI-verified cohort of apparently sporadic patients with lacunar infarct.MethodsCaucasian patients with lacunar infarction, aged ≤70 years (mean age 56.7 (SD8.6)), were recruited from 72 specialist stroke centres throughout the UK as part of the Young Lacunar Stroke DNA Resource. Patients with a previously confirmed monogenic cause of stroke were excluded. All MRI’s and clinical histories were reviewed centrally. Screening was performed for NOTCH3 and GLA mutations.ResultsOf 994 subjects five had pathogenic NOTCH3 mutations (R169C, R207C, R587C, C1222G and C323S) all resulting in loss or gain of a cysteine in the NOTCH3 protein. All five patients had confluent leukoaraiosis (Fazekas grade ≥2). CADASIL prevalence overall was 0.5% (95% CI 0.2%-1.1%) and among cases with confluent leukoaraiosis 1.5% (95% CI 0.6%-3.3%). No classic pathogenic FD mutations were found; one patient had a missense mutation (R118C), associated with late-onset FD.ConclusionCADASIL cases are rare and only detected in SVD patients with confluent leukoaraiosis. No definite FD cases were detected.

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“…NOTCH3 kodiert für einen Transmembranrezeptor, der sich histopathologisch in den Gefäßwänden betroffener Patienten ablagert [52]. Elektronenmikroskopisch zeigt sich in diesem Be-▶ Tab.…”

Section: Cadasilunclassified

Zerebrale Mikroangiopathien

Düring

Opherk

2018

Akt Neurol

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ZusammenfassungZerebrale Mikroangiopathien, Erkrankungen der kleinen Gefäße (perforierende Arterien und Arteriolen, Kapillaren, Venolen) des Gehirns, sind häufige Ursachen von Schlaganfall und vaskulärer Demenz. Die häufigste Form ist alters- und hypertonieassoziiert, die genauen Pathomechanismen sind jedoch weitgehend unbekannt. Weitere relevante Formen sind die zerebrale Amyloidangiopathie und monogen vererbte Mikroangiopathien, wie bspw. CADASIL als häufigste erbliche Schlaganfallerkrankung. An klinischen Manifestationen finden sich akute (ischämischer oder hämorrhagischer Schlaganfall) und chronische Symptome. Zu letzteren zählen eine Gangstörung, affektive Symptome und eine vaskuläre kognitive Störung mit Defiziten vorwiegend im Bereich der Exekutivfunktionen. In der MRT finden sich charakteristische Gewebeläsionen, u. a. konfluierende T2-Hyperintensitäten (Leukenzephalopathie), Lakunen, Mikroblutungen und kortikale Mikroinfarkte. Zudem kommt es im Verlauf zu einer Gehirnatrophie. Differenzialdiagnostisch müssen die verschiedenen Formen der Mikroangiopathie voneinander abgegrenzt werden, da dies ggf. therapeutische Konsequenzen hat. Ferner stellen entzündliche ZNS-Erkrankungen und Leukodystrophien mögliche Differenzialdiagnosen dar. Therapeutisch steht die Optimierung des Gefäßrisikoprofils im Vordergrund.

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Cysteine-Sparing CADASIL Mutations in NOTCH3 Show Proaggregatory Properties In Vitro

Cited by 44 publications

References 37 publications

Cross-talk between redox signalling and protein aggregation

Cross-talk between redox signalling and protein aggregation

Prevalence of CADASIL and Fabry Disease in a Cohort of MRI Defined Younger Onset Lacunar Stroke

Zerebrale Mikroangiopathien

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