The molecular organization and function of paranodal septate junctions

Close communication between axons and glial cells is required and necessary for maturation, organization and maintenance of the nervous system. The axon provides signals to promote differentiation, survival and proliferation of both oligodendrocytes and Schwann cells in the central and peripheral nervous systems respectively, while providing instructions to regulate myelin thickness. Conversely, glial cells provide reciprocal signals that regulate and control axonal mechanisms such as axonal thickness and transport. The combined efforts of glial and axonal signals result in a mature myelinated fiber that has a structural organization optimal for a maximum conduction velocity. One characteristic feature of myelinated fibers is their ability to organize specialized domains with distinctive molecular and structural characteristics. The myelinated domains include the node of Ranvier, the paranodal junction, the juxtaparanodal junction and the internodal region. This domain organization is a result of the fine bi-directional communication between the axon and the overlying glial cell. The paranodal axo-glial junction is a complex of proteins including: NCP1, Contactin (CN), Neurofascin 155 (NF155) and band 4.1B. NF155 is expressed by the overlying glial cell while the others are clustered on the axonal membrane. All proteins are necessary for the maintenance and establishment of the paranodal domain and provide a link to the axonal cytoskeleton. We and others have previously characterized two knockout mice (NCP1 and CGT) that display several signs of cerebellar deficits, including abnormal motor coordination, tremors at rest and ataxia. These knockouts share the same phenotypes one of which is their inability to form paranodal junctions properly. Interestingly NCP1 is an axonal protein and CGT is a glial protein suggesting a common mechanism of action by both cell types and the importance of axo-glial interactions in proper axonal development and organization. The goal of this project is to further understand the role, molecular composition and organization of axo-glial junctions in vertebrate systems, in particular the paranodal junction of myelinated nerve fibers. We will use these two knockout mouse model systems to identify new key components that play a role in establishing a link between the axon and glial cells

No effect of genetic deletion of contactin-associated protein (CASPR) on axonal orientation and synaptic plasticity

Myelinated axons are endowed with a specialized domain structure that is essential for saltatory action potential conduction. The paranodal domain contains the axoglial junctions and displays a unique ultrastructure that resembles the invertebrate septate junctions (SJs). Biochemical characterizations of the paranodal axoglial SJs have identified several molecular components that include Caspr and contactin (Cont) on the axonal side and neurofascin 155 kDa (NF155) isoform on the glial side. All these proteins are essential for the formation of the axoglial SJs. Based on the interactions between Caspr and Cont and their colocalization in the CA1 synaptic areas, it was proposed that the synaptic function of Cont requires Caspr. Here we have extended the phenotypic analysis of CASPR mutants to address further the role of Caspr at the axoglial SJs and also in axonal orientation and synaptic plasticity. We report that, in CASPR mutants, the smooth endoplasmic reticulum (SER) forms elongated membranous complexes that accumulate at the nodal/ paranodal region and stretch into the juxtaparanodal region, a defect that is consistent with the paranodal disorganization. We show that the cerebellar microorganization is unaffected in CASPR mutants. We also demonstrate that Caspr function is not essential for normal CA1 synaptic transmission and plasticity. Taken together with previous findings, our results highlight that the Caspr/ Cont complex is essential for the formation of axoglial SJs, whereas Cont may regulate axonal orientation and synaptic plasticity independent of its association with Caspr

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)