Expression of microRNAs in cerebrospinal fluid of dogs with central nervous system disease

Abstract In this pilot study we investigated the expression of 14 microRNAs in the cerebrospinal fluid (CSF) of dogs with neoplastic, inflammatory and degenerative disorders affecting the central nervous system (CNS). CSF microRNA (miRNA) expression profiles were compared to those from dogs with neurological signs but no evidence of structural or inflammatory CNS disease. Seven miRNAs were easily detected in all samples: miR-10b-5p, miR-19b, miR-21-5p, miR-30b-5p, miR-103a-3p, miR-124, and miR-128-3p. Expression of miR-10b-5p was significantly higher in the neoplastic group compared to other groups. There was no relation between miRNA expression and either CSF nucleated cell count or CSF protein content. Higher expression of miR-10b-5p in the neoplastic group is consistent with previous reports in human medicine where aberrant expression of miR-10b is associated with various neoplastic diseases of the CNS

Molecular Mechanism of Capacitative Calcium Entry Deficits in Familial Alzheimer’s Disease

Poster PresentationPresenilin (PS) is the catalytic subunit of the gamma-secretase which is responsible for the cleavage of amyloid precursor protein to form beta amyloid (Aβ). Mutations in PS associated with familial Alzheimer’s disease (FAD) increase the Aβ plaques formation in the brain and cause neurodegeneration. Apart from this, FAD-linked PS mutations have been demonstrated to disrupt intracellular calcium (Ca2+) regulation. Accumulating evidence suggests that Ca2+ disruption may play a proximal role in the AD pathogenesis. Mutant PS exaggerated Ca2+ release from the endoplasmic reticulum (ER). It also attenuated Ca2+ entry through the capacitative Ca2+ entry (CCE) pathway, yet, the mechanism is not fully understood. Using a human neuroblast cell line SH-SY5Y and Ca2+ imaging technique, we observed CCE deficits in FAD-linked PS1-M146L retroviral infected cell. The attenuation of CCE in PS1 mutant cells was not mediated by the down-regulation of STIM1 and Orai1 expression, the known essential molecular players in the CCE pathway. Instead, we identified a molecular interaction between PS and STIM1 proteins by immunoprecipitation. On the other hand, immunofluorescence staining showed a significant reduction in puncta formation after ER Ca2+ depleted by thapsigargin in cells infected with PS1-M146L as compared to the wild type PS1 infected cells. Taken together, our results suggest a molecular mechanism for the CCE deficits in FAD associated with PS1 mutations. The interaction of mutant PS1 with STIM1 exerts a negative impact on its oligomerization and/or its interaction with Orai1. Our results may suggest molecular targets for the development of therapeutic agents that help to treat the disease.published_or_final_versio

International Veterinary Epilepsy Task Force recommendations for a veterinary epilepsy-specific MRI protocol

Epilepsy is one of the most common chronic neurological diseases in veterinary practice. Magnetic resonance imaging (MRI) is regarded as an important diagnostic test to reach the diagnosis of idiopathic epilepsy. However, given that the diagnosis requires the exclusion of other differentials for seizures, the parameters for MRI examination should allow the detection of subtle lesions which may not be obvious with existing techniques. In addition, there are several differentials for idiopathic epilepsy in humans, for example some focal cortical dysplasias, which may only apparent with special sequences, imaging planes and/or particular techniques used in performing the MRI scan. As a result, there is a need to standardize MRI examination in veterinary patients with techniques that reliably diagnose subtle lesions, identify post-seizure changes, and which will allow for future identification of underlying causes of seizures not yet apparent in the veterinary literature. There is a need for a standardized veterinary epilepsy-specific MRI protocol which will facilitate more detailed examination of areas susceptible to generating and perpetuating seizures, is cost efficient, simple to perform and can be adapted for both low and high field scanners. Standardisation of imaging will improve clinical communication and uniformity of case definition between research studies. A 6–7 sequence epilepsy-specific MRI protocol for veterinary patients is proposed and further advanced MR and functional imaging is reviewed

Hypothesis-driven genome-wide association studies provide novel insights into genetics of reading disabilities

Peer reviewe

Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap with Bipolar Disorder, Major Depression and Schizophrenia

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

Peer reviewe

Applying polygenic risk scoring for psychiatric disorders to a large family with bipolar disorder and major depressive disorder

Psychiatric disorders are thought to have a complex genetic pathology consisting of interplay of common and rare variation. Traditionally, pedigrees are used to shed light on the latter only, while here we discuss the application of polygenic risk scores to also highlight patterns of common genetic risk. We analyze polygenic risk scores for psychiatric disorders in a large pedigree (n similar to 260) in which 30% of family members suffer from major depressive disorder or bipolar disorder. Studying patterns of assortative mating and anticipation, it appears increased polygenic risk is contributed by affected individuals who married into the family, resulting in an increasing genetic risk over generations. This may explain the observation of anticipation in mood disorders, whereby onset is earlier and the severity increases over the generations of a family. Joint analyses of rare and common variation may be a powerful way to understand the familial genetics of psychiatric disorders

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies