Update: Cerebral cavernous malformation pathogenesis

Cerebral cavernous malformation pathogenesis

Genes mutated in cerebral cavernous malformation (CCM) encode proteins that modulate junction formation between vascular endothelial cells.

Most cerebral cavernous malformations are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2(MGC4607), or CCM3 (PDCD10).

How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 1).

Although a role for these three genes in the formation of these intracranial vascular lesions has been established since the 1990s, additional works have further elucidated the molecular mechanisms by which mutations in these genes and the resultant aberrant proteins interact, leading to the formation of CCMs.

Therefore, it is reasonable to assume that a molecular pathway exists that requires all three proteins to function together correctly for proper cellular function. Moreover, research is demonstrating how each component protein is capable of interacting with numerous other signaling and cytoskeletal molecules allowing for a diverse range of functions in molecular signaling pathways via unique protein–protein interactions.

Significant research findings from 2000 to 2015 have further enhanced our understanding of the pathogenesis of CCM formation. The use of advanced sequencing technologies to characterize genomic mutations and the identification of new signaling pathways and protein–protein interactions have led to great strides in understanding the molecular genetics involved in the development of CCMs. However, many unanswered questions remain, and future studies are clearly needed to improve our understanding of CCM pathogenesis. “Gene to protein to disease” mechanisms involved in the pathogenesis of CCMs should shed further light on potential therapeutic targets. 2).

The Phosphoinositide 3 kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression.

Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment 3).


Studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics 4).

CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified.


Tang et al. identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of cerebral cavernous malformationformation. Activation of TLR4 by Gram negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment 5).


In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need 6).

References

1) , 4)

Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID: 27027284; PubMed Central PMCID: PMC4864035.
2)

Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral Cavernous Malformations: Review of the Genetic and Protein-Protein Interactions Resulting in Disease Pathogenesis. Front Surg. 2016 Nov 14;3:60. Review. PubMed PMID: 27896269.
3)

Kar S, Samii A, Bertalanffy H. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev. 2015 Apr;38(2):229-36; discussion 236-7. doi: 10.1007/s10143-014-0597-8. Epub 2014 Nov 19. PubMed PMID: 25403688.
5)

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 10. doi: 10.1038/nature22075. [Epub ahead of print] PubMed PMID: 28489816.
6)

Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E, Yonas H, Pasqualini R, Arap W. Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review. JAMA Neurol. 2018 Nov 26. doi: 10.1001/jamaneurol.2018.3634. [Epub ahead of print] PubMed PMID: 30476961.

Book: Controversial Pain Syndromes of the Arm: Pathogenesis and Surgical Treatment of Resistant Cases

Controversial Pain Syndromes of the Arm: Pathogenesis and Surgical Treatment of Resistant Cases
By Albrecht Wilhelm

Controversial Pain Syndromes of the Arm: Pathogenesis and Surgical Treatment of Resistant Cases

List Price: $59.99
This concise, well-illustrated monograph explains the true pathogenesis, hitherto unsolved, of five key pain syndromes of the arm and describes diagnosis, indications for surgery, surgical techniques, and results. The syndromes in question are tennis elbow, golf elbow, proximal radial nerve compression syndrome, so-called coracoiditis, and Sudeck’s dystrophy. In each case, the neurogenic pathogenesis is identified and deficiencies of other interpretations, for example that these conditions are the result of degenerative processes, are discussed. Appropriate surgical techniques in resistant cases are described in the context of pathogenesis, and treatment outcomes are documented. The fact that these outcomes are excellent in the large majority of cases may be taken as support for the author’s interpretation of pathogenesis. This book will be informative and instructive for all hand, orthopedic, trauma, plastic, general, and neurosurgeons as well as neurologists and hand therapists.
About the Author
Albrecht Wilhelm was born in 1929 in Braunau, Bohemia (now in the Czech Republic). He studied at Würzburg and Munich Universities and in 1955 was awarded his PhD (magna cum laude). In spring 1954 he embarked on an internship in the surgical department of Würzburg University and the results obtained with surgical methods that he subsequently developed in Würzburg formed the basis for his Habilitationsschrift, “Joint Denervation and its Anatomical Basis – A New Principle in Hand Surgery” (1966). In 1970 Dr. Wilhelm was appointed Professor of Surgery and also assumed responsibility for the Surgical Department at Aschaffenburg Hospital. Throughout his career, Dr. Wilhelm has had a keen interest in hand surgery and surgery of peripheral nerves. He has authored 139 scientific publications, 32 of which have been book contributions. He has developed 20 new surgical techniques, including 18 relating to the upper extremity and has provided solutions to the disputed pathogenesis of various conditions. Since his retirement in 1994 he has continued to conduct scientific research and voluntary surgical activities. Dr. Wilhelm has been the recipient of various honors: He received the Federal Medal in 1989. He served as President of the German Society of Hand Surgery (DGH) in 1992 and was made a member of honor of the society in 1994. He was named as an IFSSH “Pioneer of Hand Surgery” in 2004 and became a member of honor of the DAH (“German-Speaking Hand Surgery Association”) in 2013.

Product Details

  • Published on: 2015-10-12
  • Original language: English
  • Number of items: 1
  • Dimensions: 6.46″ h x .59″ w x 9.61″ l, .0 pounds
  • Binding: Hardcover
  • 154 pages

Cerebral arteriovenous malformations: Pathogenesis Update

 

The pathogenesis of cerebral arteriovenous malformations (cAVMs) is still not well understood. Generally, cAVMs are thought to be congenital lesions originating prenatally.

AVMs are usually congenital and belong to the RASopathies. The genetic transmission patterns of AVM, if any, are unknown. AVM is not generally thought to be an inherited disorder, unless in the context of a specific hereditary syndrome.
A long-held dogma in neurosurgery is that parenchymal arteriovenous malformations (AVMs) are congenital. However, there is no strong evidence supporting this theory. An increasing number of documented cases of de novo formation of parenchymal AVMs cast doubt on their congenital nature and suggest that indeed the majority may form after birth. Further evidence suggesting the postnatal development of parenchymal AVMs comes from the exceedingly rare diagnosis of these lesions in utero despite the widespread availability of high-resolution imaging modalities such as ultrasound and fetal MRI. The exact mechanism of AVM formation has yet to be elucidated, but most likely involves genetic susceptibility and environmental triggering factors 1).

Molecular and cellular biology

A PubMed search was performed using the key words “genetic,” “molecular,” “brain,” “cerebral,” “arteriovenous,” “malformation,” “rupture,” “management,” “embolization,” and “radiosurgery.” Only English-language papers were considered. The reference lists of all papers selected for full-text assessment were reviewed.
Current concepts in genetic polymorphisms, growth factors, angiopoietins, apoptosis, endothelial cells, pathophysiology, clinical syndromes, medical treatment (including tetracycline and microRNA-18a), radiation therapy, endovascular embolization, and surgical treatment as they apply to AVMs are discussed.
Understanding the complex cellular biology, physiology, hemodynamics, and flow-related phenomena of AVMs is critical for defining and predicting their behavior, developing novel drug treatments, and improving endovascular and surgical therapies 2).

1) Morales-Valero SF, Bortolotti C, Sturiale CL, Lanzino G. Are parenchymal AVMs congenital lesions? Neurosurg Focus. 2014 Sep;37(3):E2. doi:10.3171/2014.6.FOCUS14234. PubMed PMID: 25175439.
2) Rangel-Castilla L, Russin JJ, Martinez-Del-Campo E, Soriano-Baron H, Spetzler RF, Nakaji P. Molecular and cellular biology of cerebral arteriovenous malformations: a review of current concepts and future trends in treatment. Neurosurg Focus. 2014 Sep;37(3):E1. doi: 10.3171/2014.7.FOCUS14214. PubMed PMID: 25175428.
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