The human brain somatostatin interactome: SST binds selectively to P-type family ATPases.

Somatostatin (SST) is a cyclic peptide that is understood to inhibit the release of hormones and neurotransmitters from a variety of cells by binding to one of five canonical G protein-coupled SST receptors (SSTR1 to SSTR5). Recently, SST was also observed to interact with the amyloid beta (Aß) peptide and affect its aggregation kinetics, raising the possibility that it may bind other brain proteins. Here we report on an SST interactome analysis that made use of human brain extracts as biological source material and incorporated advanced mass spectrometry workflows for the relative quantitation of SST binding proteins. The analysis revealed SST to predominantly bind several members of the P-type family of ATPases. Subsequent validation experiments confirmed an interaction between SST and the sodium-potassium pump (Na+/K+-ATPase) and identified a tryptophan residue within SST as critical for binding. Functional analyses in three different cell lines indicated that SST might negatively modulate the K+ uptake rate of the Na+/K+-ATPase.

DICER1 gene mutations in endocrine tumors.

In this review, the importance of the DICER1 gene in the function of endocrine cells is discussed. There is conclusive evidence that DICER1 mutations play a crucial role in the development, progression, cell proliferation, therapeutic responsiveness and behavior of several endocrine tumors. We review the literature of DICER1 gene mutations in thyroid, parathyroid, pituitary, pineal gland, endocrine pancreas, paragangliomas, medullary, adrenocortical, ovarian and testicular tumors. Although significant progress has been made during the last few years, much more work is needed to fully understand the significance of DICER1 mutations.

Somatostatin in Alzheimer's disease: A new Role for an Old Player.

The amyloid beta (Aß) peptide is central to the pathogenesis of Alzheimer's disease (AD). Insights into Aß-interacting proteins are critical for understanding the molecular mechanisms underlying Aß-mediated toxicity. We recently undertook an in-depth in vitro interrogation of the Aß1-42 interactome using human frontal lobes as the biological source material and taking advantage of advances in mass spectrometry performance characteristics. These analyses uncovered the small cyclic neuropeptide somatostatin (SST) to be the most selectively enriched binder to oligomeric Aß1-42. Subsequent validation experiments revealed that SST interferes with Aß fibrillization and promotes the formation of Aß assemblies characterized by a 50-60 kDa SDS-resistant core. The distributions of SST and Aß overlap in the brain and SST has been linked to AD by several additional observations. This perspective summarizes this body of literature and draws attention to the fact that SST is one of several neuropeptide hormones that acquire amyloid properties before their synaptic release. The latter places the interaction between SST and Aß among an increasing number of observations that attest to the ability of amyloidogenic proteins to influence each other. A model is presented which attempts to reconcile existing data on the involvement of SST in the AD etiology.

Alpha subunit in clinically non-functioning pituitary adenomas: An immunohistochemical study.

Pituitary adenomas may be classified as either functioning or non-functioning, depending on whether excess hormone secretion can be clinically identified. Of the six hormones produced in the anterior pituitary, TSH, FSH and LH are known as glycoproteins and contain two subunits (α and ß). While α-subunit is identical within all of them, each ß-subunit is unique and biologically specific. Independently, the α- and ß-subunits are inactive and only induce a hormonal response when they are non-covalently associated. Studies have shown that in certain cases, pituitary adenomas may abnormally secrete only α-subunit, detectable in the serum or through immunohistochemical analysis. In the present study, we examined α-subunit immunoexpression in surgically removed non-functioning pituitary adenomas and analyzed its prognostic value. Results showed that expression of α-subunit in clinically non-functioning pituitary adenomas is not a rare occurrence. While there were no age/gender differences between tumors that expressed α-subunit and those that did not, α-subunit immunonegative adenomas presented with suprasellar extension more frequently and had an Ki67 proliferation greater than 3%. The use of immunohistochemical techniques to determine the presence of α-subunit may provide information on tumor cell proliferation and biologic behavior. To fully understand the role of α-subunit in pituitary adenomas more work is needed.

Somatostatin binds to the human amyloid ß peptide and favors the formation of distinct oligomers.

The amyloid ß peptide (Aß) is a key player in the etiology of Alzheimer disease (AD), yet a systematic investigation of its molecular interactions has not been reported. Here we identified by quantitative mass spectrometry proteins in human brain extract that bind to oligomeric Aß1-42 (oAß1-42) and/or monomeric Aß1-42 (mAß1-42) baits. Remarkably, the cyclic neuroendocrine peptide somatostatin-14 (SST14) was observed to be the most selectively enriched oAß1-42 binder. The binding interface comprises a central tryptophan within SST14 and the N-terminus of Aß1-42. The presence of SST14 inhibited Aß aggregation and masked the ability of several antibodies to detect Aß. Notably, Aß1-42, but not Aß1-40, formed in the presence of SST14 oligomeric assemblies of 50 to 60 kDa that were visualized by gel electrophoresis, nanoparticle tracking analysis and electron microscopy. These findings may be relevant for Aß-directed diagnostics and may signify a role of SST14 in the etiology of AD.

Cerebrospinal fluid leaks in extended endoscopic transsphenoidal surgery: covering all the angles.

Following extended endoscopic transsphenoidal approach (EETSA), cerebrospinal fluid (CSF) leak rate has been reported in the range of 5-50 %. Novel closure techniques, such as the nasoseptal flap and other multilayered repairs improved the outcomes significantly but took most of our focus. Little attention, however, was given to other aspects of the equation such as nasal support-to support the heavy weight of such repairs-and lumbar drains. These are important because they diminish the forces acting on both sides of the repair, hence covering all the angles. We reviewed data of 98 consecutive patients who underwent an EETSA between 1999 and 2014. We analyzed the rates of CSF leak throughout the years and with every modification added to our closure technique. Common pathologies encountered were invasive adenomas, meningiomas, chordomas, and craniopharyngiomas. CSF leak occurred overall in five patients (5.1 %). The nasoseptal flap decreased the rate of CSF leak but not significantly (P = 0.112), while placing a nasal trumpet to support our repair resulted in significant decrease in CSF leak rate (P = 0.0013). In the last 2 years of our series, when all modifications took place and all angles were covered, there was one leak in 35 cases (2.8 %). A protocol that covers all the angles by a good multilayered repair (regardless of its type and materials) while diminishing the forces acting on both sides of the repair leads to a minimal rate of CSF leak. No principle alone is effective individually.

Strains of Pathological Protein Aggregates in Neurodegenerative Diseases.

The presence of protein aggregates in the brain is a hallmark of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Considerable evidence has revealed that the pathological protein aggregates in many neurodegenerative diseases are able to self-propagate, which may enable pathology to spread from cell-to-cell within the brain. This property is reminiscent of what occurs in prion diseases such as Creutzfeldt-Jakob disease. A widely recognized feature of prion disorders is the existence of distinct strains of prions, which are thought to represent unique protein aggregate structures. A number of recent studies have pointed to the existence of strains of protein aggregates in other, more common neurodegenerative illnesses such as AD, PD, and related disorders. In this review, we outline the pathobiology of prion strains and discuss how the concept of protein aggregate strains may help to explain the heterogeneity inherent to many human neurodegenerative disorders.