scholarly journals Systems-wide analysis unravels the new roles of CCM signal complex (CSC)

2019 ◽  
Author(s):  
Johnathan Abou-Fadel ◽  
Mariana Vasquez ◽  
Brian Grajeda ◽  
Cameron Ellis ◽  
Jun Zhang
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Rna Seq ◽  
Vascular Integrity ◽  
Cavernous Malformations ◽  
Signaling Complex ◽  
Protein Levels ◽  
Global View ◽  
Cellular Factors ◽  
Β4 Integrin ◽  
Increased Susceptibility

AbstractCerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial capillaries that result in increased susceptibility to stroke. Three genes have been identified as causes of CCMs; KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3); one of them is disrupted in most CCM cases. It was demonstrated that both CCM1 and CCM3 bind to CCM2 to form a CCM signaling complex (CSC) to modulate angiogenesis. In this report, we deployed both RNA-seq and proteomic analysis of perturbed CSC after depletion of one of three CCM genes to generate interactomes for system-wide studies. Our results demonstrated a unique portrait detailing alterations in angiogenesis and vascular integrity. Interestingly, only in-direct overlapped alterations between RNA and protein levels were detected, supporting the existence of multiple layers of regulation in CSC cascades. Notably, this is the first report identifying that both β4 integrin and CAV1 signaling are downstream of CSC, conveying the angiogenic signaling. Our results provide a global view of signal transduction modulated by the CSC, identifies novel regulatory signaling networks and key cellular factors associated with CSC.

scholarly journals Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

2021 ◽  
Author(s):  
Daniel A. Snellings ◽  
Romuald Girard ◽  
Rhonda Lightle ◽  
Abhinav Srinath ◽  
Sharbel Romanos ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Clonal Population ◽  
Signaling Complex ◽  
Venous Anomalies ◽  
Brain Vasculature ◽  
Developmental Venous Anomalies ◽  
Single Nucleus ◽  
The Brain

AbstractCerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically in otherwise healthy individuals, or be inherited by autosomal dominant mutations in the genes that encode the proteins of the CCM signaling complex (KRIT1, CCM2, or PDCD10)1–4. CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene5–8. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis9–11; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM. Using single-nucleus DNA sequencing, we show that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. Furthermore, we identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). It has long been known that sporadic CCM often develop in the vicinity of a DVA. However, the underlying cause of this association is unknown12–14. In this first report of the molecular pathology of CCM-associated DVA, we find that the identical PIKC3A mutation is found in both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.

scholarly journals Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity

2010 ◽  
Vol 189 (1) ◽  
pp. i2-i2
Author(s):  
Rebecca A. Stockton ◽  
Robert Shenkar ◽  
Issam A. Awad ◽  
Mark H. Ginsberg
Keyword(s):  
Rho Kinase ◽  
Cerebral Cavernous Malformations ◽  
Vascular Integrity ◽  
Cavernous Malformations

scholarly journals A Series of 14 Representative Presentations of Cerebral Cavernous Malformations

2021 ◽  
pp. 101298
Author(s):  
Ryan Hudnall ◽  
Eric X. Chen ◽  
Patrick J Opperman ◽  
Sean Kelly ◽  
Justin A. Cramer ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations

scholarly journals A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

2021 ◽  
Author(s):  
Vega García-Escudero ◽  
Daniel Ruiz-Gabarre ◽  
Ricardo Gargini ◽  
Mar Pérez ◽  
Esther García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Rna Seq ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Post Translational Modifications ◽  
Protein Levels ◽  
Tau Isoform ◽  
Human Specific

AbstractTauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

Genotype-phenotype correlations in cerebral cavernous malformations patients

2006 ◽  
Vol 60 (5) ◽  
pp. 550-556 ◽  
Author(s):  
Christian Denier ◽  
Pierre Labauge ◽  
Françoise Bergametti ◽  
Florence Marchelli ◽  
Florence Riant ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations

Abstract 159: Exceptional Aggressiveness of CCM3 Phenotype

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Tania J Rebeiz ◽  
Abdul Ghani Mikati ◽  
Darlene Simkhin ◽  
Cornelia Lee ◽  
Amy Akers ◽  
...  
Keyword(s):  
Spontaneous Mutation ◽  
Mutation Screening ◽  
High Sensitivity ◽  
Skin Lesions ◽  
Cerebral Cavernous Malformations ◽  
Cognitive Disability ◽  
Cavernous Malformations ◽  
Patient Advocacy Group ◽  
Sporadic Cases

Introduction: Familial forms of cerebral cavernous malformations (CCM) account for about 1/3 of cases, involving autosomal dominant inheritance at 1 of 3 gene loci. Few studies have examined any special features of the rarest cases with CCM3 (PDCD10 ) mutation at q3, constituting <15 % of probands genotyped by sequential mutation screening, and <2% of CCM cases at large. Hypothesis: We hypothesize that CCM3 cases have unique phenotypic features not recognized in the more common CCM1 and 2 families, or in sporadic cases. Methods: Twelve probands including 17 subjects with confirmed CCM3 mutations were prospectively enrolled through systematic facilitated referral by the patient advocacy group Angioma Alliance. Clinical features were catalogued, including high sensitivity susceptibility weighted imaging (SWI). Rates of overt hemorrhage were determined based on adjudicated criteria. Comparisons were made to systematic literature review of natural history data on non-CCM3 cases. Results: The first overt hemorrhage occurred most often in the 1st decade of life (mean age 5.8). Nine of 17 subjects (52%) suffered 30 overt hemorrhages, with an estimated incidence of 6.7 % /patient/year based on exposure risk since birth, and 17% /patient/year based on risk since first symptom onset. Lesion burden on SWI was exceptionally high, >100 lesions in 28%, and > 20 lesions in 72% of cases, respectively. Adjusted bleed rate was <0.5% /lesion/year. New SWI lesions formed at a rate of 2.7/patient/year in prospective follow-up, and 1.8/patient/year based on years since birth. Scoliosis was found in 47% (an association not recognized previously), skin lesions in 29.4%, and brain tumors in 29.4% of cases, respectively. Cognitive disability affected 47% of cases, mostly in association with high lesion burden. Six of 15 cases with parental screening (40%) represented a spontaneous mutation. Conclusion: CCM3 is exceptionally aggressive compared to other familial and sporadic CCM. High risks of bleeding and cognitive disability mostly reflect severe lesion burden early in life, rather than a higher risk per lesion. These results will inform the design of clinical trials, urgently needed to address this unique CCM cohort.

scholarly journals Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations

2013 ◽  
Vol 17 (3) ◽  
pp. 407-418 ◽  
Author(s):  
Chao You ◽  
Ibrahim Erol Sandalcioglu ◽  
Philipp Dammann ◽  
Ute Felbor ◽  
Ulrich Sure ◽  
...  
Keyword(s):  
Notch Signalling ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations
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