Genetic Screen in Adult Drosophila Reveals That dCBP Depletion in Glial Cells Mitigates Huntington Disease Pathology through a Foxo-Dependent Pathway.

Huntington's disease (HD) is a progressive and fatal autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the huntingtin gene (HTT). In spite of considerable efforts, there is currently no treatment to stop or delay the disease. Although HTT is expressed ubiquitously, most of our knowledge has been obtained on neurons. More recently, the impact of mutant huntingtin (mHTT) on other cell types, including glial cells, has received growing interest. It is currently unclear whether new pathological pathways could be identified in these cells compared to neurons. To address this question, we performed an in vivo screen for modifiers of mutant huntingtin (HTT-548-128Q) induced pathology in Drosophila adult glial cells and identified several putative therapeutic targets. Among them, we discovered that partial nej/dCBP depletion in these cells was protective, as revealed by strongly increased lifespan and restored locomotor activity. Thus, dCBP promotes the HD pathology in glial cells, in contrast to previous opposite findings in neurons. Further investigations implicated the transcriptional activator Foxo as a critical downstream player in this glial protective pathway. Our data suggest that combinatorial approaches combined to specific tissue targeting may be required to uncover efficient therapies in HD.

CRISPR and the Rebirth of Synthetic Biology.

Emergence of novel genome engineering technologies such as clustered regularly interspaced short palindromic repeat (CRISPR) has refocused attention on unresolved ethical complications of synthetic biology. Biosecurity concerns, deontological issues and human right aspects of genome editing have been the subject of in-depth debate; however, a lack of transparent regulatory guidelines, outdated governance codes, inefficient time-consuming clinical trial pathways and frequent misunderstanding of the scientific potential of cutting-edge technologies have created substantial obstacles to translational research in this area. While a precautionary principle should be applied at all stages of genome engineering research, the stigma of germline editing, synthesis of new life forms and unrealistic presentation of current technologies should not arrest the transition of new therapeutic, diagnostic or preventive tools from research to clinic. We provide a brief review on the present regulation of CRISPR and discuss the translational aspect of genome engineering research and patient autonomy with respect to the "right to try" potential novel non-germline gene therapies.

On the Brink of Shifting Paradigms, Molecular Systems Engineering Ethics Needs to Take a Proactive Approach.

Molecular Systems Engineering (MSE) is a paradigm shift in both engineering and life sciences. While the field is still in its infancy the perspectives of MSE in revolutionising technology is promising. MSE will offer a wide range of applications in clinical, biotechnological and engineering fields while simultaneously posing serious questions on the ethical and societal aspects of such technology. The moral and societal aspects of MSE need systematic investigation from scientific and social perspectives. In a democratic setting, the societal outcomes of MSE's cutting-edge technology need to be consulted and influenced by society itself. For this purpose MSE needs inclusive public engagement strategies that bring together the public, ethicists, scientists and policy makers for optimum flow of information that maximizes the impact of public engagement. In this report we present an MSE consortium and its ethics framework for establishing a proactive approach in the study of the ethics of MSE technology.

Plasticity of local GABAergic interneurons drives olfactory habituation.

Despite its ubiquity and significance, behavioral habituation is poorly understood in terms of the underlying neural circuit mechanisms. Here, we present evidence that habituation arises from potentiation of inhibitory transmission within a circuit motif commonly repeated in the nervous system. In Drosophila, prior odorant exposure results in a selective reduction of response to this odorant. Both short-term (STH) and long-term (LTH) forms of olfactory habituation require function of the rutabaga-encoded adenylate cyclase in multiglomerular local interneurons (LNs) that mediate GABAergic inhibition in the antennal lobe; LTH additionally requires function of the cAMP response element-binding protein (CREB2) transcription factor in LNs. The odorant selectivity of STH and LTH is mirrored by requirement for NMDA receptors and GABA(A) receptors in odorant-selective, glomerulus-specific projection neurons(PNs). The need for the vesicular glutamate transporter in LNs indicates that a subset of these GABAergic neurons also releases glutamate. LTH is associated with a reduction of odorant-evoked calcium fluxes in PNs as well as growth of the respective odorant-responsive glomeruli. These cellular changes use similar mechanisms to those required for behavioral habituation. Taken together with the observation that enhancement of GABAergic transmission is sufficient to attenuate olfactory behavior, these data indicate that habituation arises from glomerulus-selective potentiation of inhibitory synapses in the antennal lobe. We suggest that similar circuit mechanisms may operate in other species and sensory systems.

Accessibility of prison healthcare for elderly inmates, a qualitative assessment.

Aging in custody and the rising population of elderly prisoners are creating compelling challenges for criminal justice, prison and public healthcare systems. Geriatric syndrome and higher prevalence of co-morbidities amongst older inmates result in heightened vulnerability in prison environments. Empirical research addressing older adults' access to medical care in detention is scarce; therefore, this study assessed access to medical care in prison from the perspective of older prisoners in Switzerland. We interviewed a sample of 35 older inmates (average age 61 years) on their experience of healthcare accessibility in prison; data were qualitatively analysed and major themes regarding evaluation of their access to medical services were extracted. Our findings identified three barriers to accessing health services in prison including psychological obstacles, negative consequences of healthcare utilization, and environmental hurdles. We advocate facilitating older inmates' access to medical care in order to relieve the psychological burden of seeking health services in detention and adequately informing them of their right to demand these services, thereby lessening the negative consequences of their requests. We suggest further training of prison and medical staff for better management of age-related issues in prison can ease the environmental obstacles.

Methylene Blue Partially Rescues Heart Defects in a Drosophila Model of Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a Polyglutamine disease caused by the presence of CAG repeats in the first exon of Huntingtin (Htt), a large protein with multiple functions. In addition to neurodegeneration of specific brain regions, notably the striatum, HD also shows alterations in peripheral tissues, such as the heart, skeletal muscles or peripheral endocrine glands. Mutant Huntingtin (mHtt)-driven mitochondrial impairment may underlie some of the CNS and peripheral tissues dysfunctions, especially in tissues with high energy demand such as the heart. OBJECTIVE: The aim of this study is to characterize two new inducible Drosophila HD heart models and to assay the therapeutic potential of methylene blue in these HD models. METHODS: We report the construction of inducible Drosophila HD heart models, expressing two Nter fragments of the protein encompassing either exon 1 or the first 171 amino acids and the characterization of heart phenotypes in vivo. RESULTS: We show that both mHtt fragments are able to impair fly cardiac function with different characteristics. Additionally, expression of mHtt, which was limited to adulthood only, leads to mild heart impairment, as opposed to a strong and age-dependent phenotype observed when mHtt expression was driven during both developmental and adult stages. We report that treatment with methylene blue (MB), a protective compound in mitochondria-related diseases, partially protects the fly's heart against mHtt-induced toxicity, but does not rescue neuronal or glial phenotypes in other fly models of HD. This may be linked to its low penetration through the fly's blood-brain barrier. CONCLUSIONS: Our data suggest that improvement of mitochondrial function by MB, or related compounds, could be an efficient therapeutic strategy to prevent cardiac failure in HD patients.