Tourette syndrome : do reduced histamine levels induce an increase in spontaneous repetitive behaviour?

Gilles de la Tourette syndrome (TS) is a disabling neuropsychiatric disorder characterised by persistent motor and vocal tics. Comorbidity of TS with other neuropsychiatric conditions such as obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and autism is frequent. TS has a significant genetic contribution and, in this regard, several susceptibility loci have been identified including the histidine decarboxylase (HDC ) gene, which encodes an enzyme that is essential for histamine synthesis. Animal models of human disease are key to identify genetic and, importantly, pharmacological modifiers of phenotypes that mimic those present in the human condition. HDC is highly conserved throughout different species including the fruit fly Drosophila melanogaster. Aiming at uncovering TS-like phenotypes, in the present study we investigated repetitive grooming behaviour in flies that have reduced histamine levels as a result of a mutation in the hdc-encoding gene. We find that histamine deficiency in Drosophila is not associated with an increase in spontaneous repetitive grooming behaviour but rather a decrease. We speculate that the grooming behaviour in Drosophila hdc knockouts is not a translationally relevant TS phenotype. Future work should investigate whether stereotypy can be induced in the same mutants after pharmacological challenge or stress induction.peer-reviewe

Genetic screen identifies a requirement for SMN in mRNA localisation within the Drosophila oocyte

Abstract Objective Spinal muscular atrophy (SMA) results from insufficient levels of the survival motor neuron (SMN) protein. Drosophila is conducive to large-scale genetic-modifier screens which can reveal novel pathways underpinning the disease mechanism. We tested the ability of a large collection of genomic deletions to enhance SMN-dependent lethality. To test our design, we asked whether our study can identify loci containing genes identified in previous genetic screens. Our objective was to find a common link between genes flagged in independent screens, which would allow us to expose novel functions for SMN in vivo. Results Out of 128 chromosome deficiency lines, 12 (9.4%) were found to consistently depress adult viability when crossed to SMN loss-of-function heterozygotes. In their majority, the enhancing deletions harboured genes that were previously identified as genetic modifiers, hence, validating the design of the screen. Importantly, gene overlap allowed us to flag genes with a role in post-transcriptional regulation of mRNAs that are crucial for determining the axes of the oocyte and future embryo. We find that SMN is also required for the correct localisation of gurken and oskar mRNAs in oocytes. These findings extend the role of SMN in oogenesis by identifying a key requirement for mRNA trafficking

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