Rapid Accumulation of Endogenous Tau Oligomers in a Rat Model of Traumatic Brain Injury: POSSIBLE LINK BETWEEN TRAUMATIC BRAIN INJURY AND SPORADIC TAUOPATHIES*

Traumatic brain injury (TBI) is a serious problem that affects millions of people in the United States alone. Multiple concussions or even a single moderate to severe TBI can also predispose individuals to develop a pathologically distinct form of tauopathy-related dementia at an early age. No effective treatments are currently available for TBI or TBI-related dementia; moreover, only recently has insight been gained regarding the mechanisms behind their connection. Here, we used antibodies to detect oligomeric and phosphorylated Tau proteins in a non-transgenic rodent model of parasagittal fluid percussion injury. Oligomeric and phosphorylated Tau proteins were detected 4 and 24 h and 2 weeks post-TBI in injured, but not sham control rats. These findings suggest that diagnostic tools and therapeutics that target only toxic forms of Tau may provide earlier detection and safe, more effective treatments for tauopathies associated with repetitive neurotrauma.     

Kinetic and Spectroscopic Studies of Bicupin Oxalate Oxidase and Putative Active Site Mutants

Ceriporiopsis subvermispora oxalate oxidase (CsOxOx) is the first bicupin enzyme identified that catalyzes manganese-dependent oxidation of oxalate. In previous work, we have shown that the dominant contribution to catalysis comes from the monoprotonated form of oxalate binding to a form of the enzyme in which an active site carboxylic acid residue must be unprotonated. CsOxOx shares greatest sequence homology with bicupin microbial oxalate decarboxylases (OxDC) and the 241-244DASN region of the N-terminal Mn binding domain of CsOxOx is analogous to the lid region of OxDC that has been shown to determine reaction specificity. We have prepared a series of CsOxOx mutants to probe this region and to identify the carboxylate residue implicated in catalysis. The pH profile of the D241A CsOxOx mutant suggests that the protonation state of aspartic acid 241 is mechanistically significant and that catalysis takes place at the N-terminal Mn binding site. The observation that the D241S CsOxOx mutation eliminates Mn binding to both the N- and C- terminal Mn binding sites suggests that both sites must be intact for Mn incorporation into either site. The introduction of a proton donor into the N-terminal Mn binding site (CsOxOx A242E mutant) does not affect reaction specificity. Mutation of conserved arginine residues further support that catalysis takes place at the N-terminal Mn binding site and that both sites must be intact for Mn incorporation into either site.     

Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate

Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whether autistic patients are more often diagnosed with neoplasms. Exome-sequencing data from the ARRA Autism Sequencing Collaboration was compared to that of a control cohort from the Exome Variant Server database revealing that rare, coding variants within oncogenes were enriched for in the ARRA ASD cohort (p<1.0x10^-8). In contrast, variants were not significantly enriched in tumor suppressor genes. Phenotypically, children and adults with ASD exhibited a protective effect against cancer, with a frequency of 1.3% vs. 3.9% (p<0.001), but the protective effect decreased with age. The odds ratio of neoplasm for those with ASD relative to controls was 0.06 (95% CI: 0.02, 0.19; p<0.0001) in the 0 to 14 age group; 0.35 (95% CI: 0.14, 0.87; p = 0.024) in the 15 to 29 age group; 0.41 (95% CI: 0.15, 1.17; p = 0.095) in the 30 to 54 age group; and 0.49 (95% CI: 0.14, 1.74; p = 0.267) in those 55 and older. Both males and females demonstrated the protective effect. These findings suggest that defects in cellular proliferation, and potentially senescence, might influence both autism and neoplasm, and already approved drugs targeting oncogenic pathways might also have therapeutic value for treating autism.     

Gatekeeper role of brain antigen‐presenting CD11c+ cells in neuroinflammation

Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigen‐presenting cells, dendritic cells. Applying intravital two‐photon microscopy, we demonstrate the gatekeeper function of CNS professional antigen‐presenting CD11c⁺ cells, which preferentially interact with Th17 cells. IL‐17 expression correlates with expression of GM‐CSF by T cells and with accumulation of CNS CD11c⁺ cells. These CD11c⁺ cells are organized in perivascular clusters, targeted by T cells, and strongly express the inflammatory chemokines Ccl5, Cxcl9, and Cxcl10. Our findings demonstrate a fundamental role of CNS CD11c⁺ cells in the attraction of pathogenic T cells into and their survival within the CNS. Depletion of CD11c⁺ cells markedly reduced disease severity due to impaired enrichment of pathogenic T cells within the CNS.     

Experimentally induced variation in neuroendocrine processes affects male reproductive behaviour,sperm characteristics and social interactions

While extensive research has focused on how social interactions evolve, the fitness consequences of the neuroendocrine mechanisms underlying these interactions have rarely been documented, especially in the wild. Here, we measure how the neuroendocrine mechanisms underlying male behaviour affect mating success and sperm competition in the ocellated wrasse (Symphodus ocellatus). In this species, males exhibit three alternative reproductive types. “Nesting males” provide parental care, defend territories and form cooperative associations with unrelated “satellites,” who cheat by sneaking fertilizations but help by reducing sperm competition from “sneakers” who do not cooperate or provide care. To measure the fitness consequences of the mechanisms underlying these social interactions, we used “phenotypic engineering” that involved administering an androgen receptor antagonist (flutamide) to wild, free‐living fish. Nesting males treated with flutamide shifted their aggression from sneakers to satellite males and experienced decreased submissiveness by sneaker males (which correlated with decreased nesting male mating success). The preoptic area (POA), a region controlling male reproductive behaviours, exhibited dramatic down‐regulation of androgen receptor (AR) and vasotocin 1a receptor (V1aR) mRNA following experimental manipulation of androgen signalling. We did not find a direct effect of the manipulation on male mating success, paternity or larval production. However, variation in neuroendocrine mechanisms generated by the experimental manipulation was significantly correlated with changes in behaviour and mating success: V1aR expression was negatively correlated with satellite‐directed aggression, and expression of its ligand arginine vasotocin (AVT) was positively correlated with courtship and mating success, thus revealing the potential for sexual selection on these mechanisms.     

Functional Access to Neuron Subclasses in Rodent and Primate Forebrain

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