Cerebral cavernous malformation 3 relieves subarachnoid hemorrhage-induced neuroinflammation in rats through inhibiting NF-kB signaling pathway.

Subarachnoid hemorrhage (SAH) is a severe acute cerebrovascular disease with high rates of disability and death. In recent years, a large number of studies has shown that early brain injury (EBI) may be a crucial cause of the poor prognosis of SAH and that microglia-mediated neuroinflammation is an important pathological process in EBI. Previous studies have indicated that tumor necrosis factor receptor-associated factor 6 (TRAF6) is involved in microglia-mediated neuroinflammation after SAH. In addition, it has been reported that cerebral cavernous malformation 3/mammalian sterile20-like kinase 4 (CCM3/MST4) directly phosphorylates TRAF6 to inhibit its ubiquitination and to limit inflammatory responses. However, the association between CCM3/MST4 and SAH has not been reported. In our present study, we established a SAH model in adult male rats through injecting autologous arterial blood into the prechiasmatic cistern. Additionally, BV-2 cells, as well as primary microglial cultures from rats treated with oxygen hemoglobin (OxyHb) for 24 h, were used as in vitro models of SAH. Then, western blot, immunofluorescence, Fluoro-JadeC staining and Enzyme-linked immunosorbent assay (ELISA) and behavioral tests was applied in this study. We observed no significant change in the level of CCM3/MST4 in brain tissues, but a markedly decline of CCM3 in microglia of rats. We also found that the protein level of CCM3 was decreased in BV-2 cells after OxyHb treatment, reaching the lowest point at 6 h post-treatment. In contrast, there was no significant change in the protein level of MST4. Additionally, we recapitulated decreased expression of CCM3 and changes in subcellular localization of CCM3 in vitro model of SAH with primary microglial cultures treated with OxyHb. Overexpression of CCM3 decreased cellular degeneration, neurocognitive impairment, NF-κB p65 level in the nuclear, and inflammatory factors level (TNF-a and IL-1ß). These results suggest that overexpression of CCM3 alleviated brain injury and neurological damage through the NF-κB signaling pathway.

First case of neutropenia and thrombocytopenia in the setting of cerebral cavernous malformation 3.

Cerebral cavernous malformation 3 (CCM3) is a vascular malformation disorder causing brain slow-flow vascular parenchymal lesions. These lesions are the result of variants in the Programmed Cell Death Protein 10 (PDCD10) gene, located on 3q26.1. We report an 8-month-old patient who was presented with seizures and intracranial abscesses and was found to have a variant of PDCD10 on whole exome sequencing, representing, to our knowledge, the youngest case of CCM3 described in the literature. Her clinical course was complicated by the development of neutropenia, requiring granulocyte colony-stimulating factor, and thrombocytopenia, requiring intermittent platelet transfusions, with later development of B acute lymphoblastic leukemia 2 years after initial presentation. This case represents the first description in the literature of hematologic complications in the setting of CCM3. We hypothesize that these hematological manifestations are the result of alterations in the actin and microtubule cytoskeleton, affecting the process of hematopoiesis in a similar fashion to the documented effect of the PDCD10 variant on neuronal migration.

STRIPAK complexes: structure, biological function, and involvement in human diseases.

The mammalian striatin family consists of three proteins, striatin, S/G2 nuclear autoantigen, and zinedin. Striatin family members have no intrinsic catalytic activity, but rather function as scaffolding proteins. Remarkably, they organize multiple diverse, large signaling complexes that participate in a variety of cellular processes. Moreover, they appear to be regulatory/targeting subunits for the major eukaryotic serine/threonine protein phosphatase 2A. In addition, striatin family members associate with germinal center kinase III kinases as well as other novel components, earning these assemblies the name striatin-interacting phosphatase and kinase (STRIPAK) complexes. Recently, there has been a great increase in functional and mechanistic studies aimed at identifying and understanding the roles of STRIPAK and STRIPAK-like complexes in cellular processes of multiple organisms. These studies have identified novel STRIPAK and STRIPAK-like complexes and have explored their roles in specific signaling pathways. Together, the results of these studies have sparked increased interest in striatin family complexes because they have revealed roles in signaling, cell cycle control, apoptosis, vesicular trafficking, Golgi assembly, cell polarity, cell migration, neural and vascular development, and cardiac function. Moreover, STRIPAK complexes have been connected to clinical conditions, including cardiac disease, diabetes, autism, and cerebral cavernous malformation. In this review, we discuss the expression, localization, and protein domain structure of striatin family members. Then we consider the diverse complexes these proteins and their homologs form in various organisms, emphasizing what is known regarding function and regulation. Finally, we explore possible roles of striatin family complexes in disease, especially cerebral cavernous malformation.