A transdisciplinary perspective of chronic stress in relation to psychopathology throughout life span development

The allostatic load (AL) model represents an interdisciplinary approach to comprehensively conceptualize and quantify chronic stress in relation to pathologies throughout the life cycle. This article first reviews the AL model, followed by interactions among early adversity, genetics, environmental toxins, as well as distinctions among sex, gender, and sex hormones as integral antecedents of AL. We next explore perspectives on severe mental illness, dementia, and caregiving as unique human models of AL that merit future investigations in the field of developmental psychopathology. A complimenting transdisciplinary perspective is applied throughout, whereby we argue that the AL model goes beyond traditional stress–disease theories toward the advancement of person-centered research and practice that promote not only physical health but also mental healt

Evaluation of Histone Deacetylases as Drug Targets in Huntington’s Disease models: Study of HDACs in brain tissues from R6/2 and CAG140 knock-in HD mouse models and human patients and in a neuronal HD cell model.

The family of histone deacetylases (HDACs) has recently emerged as important drug targets for treatment of slow progressive neurodegenerative disorders, including Huntington’s disease (HD). Broad pharmaceutical inhibition of HDACs has shown neuroprotective effects in various HD models. Here we examined the susceptibility of HDAC targets for drug treatment in affected brain areas during HD progression. We observed increased HDAC1 and decreased HDAC4, 5 and 6 levels, correlating with disease progression, in cortices and striata of HD R6/2 mice. However, there were no significant changes in HDAC protein levels, assessed in an age-dependent manner, in HD knock-in CAG140 mice and we did not observe significant changes in HDAC1 levels in human HD brains. We further assessed acetylation levels of α-tubulin, as a biomarker of HDAC6 activity, and found it unchanged in cortices from R6/2, knock-in, and human subjects at all disease stages. Inhibition of deacetylase activities was identical in cortical extracts from R6/2 and wild-type mice treated with a class II-selective HDAC inhibitor. Lastly, treatment with class I- and II-selective HDAC inhibitors showed similar responses in HD and wild-type rat striatal cells. In conclusion, our results show that class I and class II HDAC targets are present and accessible for chronic drug treatment during HD progression and provide impetus for therapeutic development of brain-permeable class- or isoform-selective inhibitors

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis

Huntington’s disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2’s role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins

SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis.

Huntington's disease (HD), an incurable neurodegenerative disorder, has a complex pathogenesis including protein aggregation and the dysregulation of neuronal transcription and metabolism. Here, we demonstrate that inhibition of sirtuin 2 (SIRT2) achieves neuroprotection in cellular and invertebrate models of HD. Genetic or pharmacologic inhibition of SIRT2 in a striatal neuron model of HD resulted in gene expression changes including significant down-regulation of RNAs responsible for sterol biosynthesis. Whereas mutant huntingtin fragments increased sterols in neuronal cells, SIRT2 inhibition reduced sterol levels via decreased nuclear trafficking of SREBP-2. Importantly, manipulation of sterol biosynthesis at the transcriptional level mimicked SIRT2 inhibition, demonstrating that the metabolic effects of SIRT2 inhibition are sufficient to diminish mutant huntingtin toxicity. These data identify SIRT2 inhibition as a promising avenue for HD therapy and elucidate a unique mechanism of SIRT2-inhibitor-mediated neuroprotection. Furthermore, the ascertainment of SIRT2's role in regulating cellular metabolism demonstrates a central function shared with other sirtuin proteins

Evolution of New Genotype of West Nile Virus in North America

Previous studies of North American isolates of West Nile virus (WNV) during 1999–2005 suggested that the virus had reached genetic homeostasis in North America. However, genomic sequencing of WNV isolates from Harris County, Texas, during 2002–2009 suggests that this is not the case. Three new genetic groups have been identified in Texas since 2005. Spread of the southwestern US genotype (SW/WN03) from the Arizona/Colorado/northern Mexico region to California, Illinois, New Mexico, New York, North Dakota, and the Texas Gulf Coast demonstrates continued evolution of WNV. Thus, WNV continues to evolve in North America, as demonstrated by selection of this new genotype. Continued surveillance of the virus is essential as it continues to evolve in the New World

A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of Sirtuin 2 Deacetylase

Sirtuin 2 (SIRT2) deacetylase-dependent inhibition mediates neuroprotective reduction of cholesterol biosynthesis in an in vitro Huntington’s disease model. This study sought to identify the first brain-permeable SIRT2 inhibitor and to characterize its cholesterol-reducing properties in neuronal models. Using biochemical sirtuin deacetylation assays, we screened a brain-permeable in silico compound library, yielding 3-(1-azepanylsulfonyl)-N-(3-bromphenyl)benzamide as the most potent and selective SIRT2 inhibitor. Pharmacokinetic studies demonstrated brain-permeability but limited metabolic stability of the selected candidate. In accordance with previous observations, this SIRT2 inhibitor stimulated cytoplasmic retention of sterol regulatory element binding protein-2 and subsequent transcriptional downregulation of cholesterol biosynthesis genes, resulting in reduced total cholesterol in primary striatal neurons. Furthermore, the identified inhibitor reduced cholesterol in cultured naïve neuronal cells and brain slices from wild-type mice. The outcome of this study provides a clear opportunity for lead optimization and drug development, targeting metabolic dysfunctions in CNS disorders where abnormal cholesterol homeostasis is implicated