Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD

Hdac6 Knock-Out Increases Tubulin Acetylation but Does Not Modify Disease Progression in the R6/2 Mouse Model of Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder for which there is no effective disease modifying treatment. Following-on from studies in HD animal models, histone deacetylase (HDAC) inhibition has emerged as an attractive therapeutic option. In parallel, several reports have demonstrated a role for histone deacetylase 6 (HDAC6) in the modulation of the toxicity caused by the accumulation of misfolded proteins, including that of expanded polyglutamine in an N-terminal huntingtin fragment. An important role for HDAC6 in kinesin-1 dependent transport of brain-derived neurotrophic factor (BDNF) from the cortex to the striatum has also been demonstrated. To elucidate the role that HDAC6 plays in HD progression, we evaluated the effects of the genetic depletion of HDAC6 in the R6/2 mouse model of HD. Loss of HDAC6 resulted in a marked increase in tubulin acetylation throughout the brain. Despite this, there was no effect on the onset and progression of a wide range of behavioural, physiological, molecular and pathological HD-related phenotypes. We observed no change in the aggregate load or in the levels of soluble mutant exon 1 transprotein. HDAC6 genetic depletion did not affect the efficiency of BDNF transport from the cortex to the striatum. Therefore, we conclude that HDAC6 inhibition does not modify disease progression in R6/2 mice and HDAC6 should not be prioritized as a therapeutic target for HD

Short-Term Striatal Gene Expression Responses to Brain-Derived Neurotrophic Factor Are Dependent on MEK and ERK Activation

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity. CONCLUSIONS: These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression

Georeferenced soil information system: assessment of database

Land-use planning is a decision-making process that facilitates the allocation of land to different uses that provide optimal and sustainable benefit. As land-use is shaped by society–nature interaction, in land-use planning different components/facets play a significant role involving soil, water, climate, animal (ruminant/ non-ruminant) and others, including forestry and the environment needed for survival of mankind. At times these components are moderated by human interference. Thus land-use planning being a dynamic phenomenon is not guided by a single factor, but by a complex system working simultaneously,which largely affects the sustainability. To address such issues a National Agricultural Innovation Project (NAIP) on ‘Georeferenced soil information system for land-use planning and monitoring soil and land quality for agriculture’ was undertaken to develop threshold values of land quality parameters for land-use planning through quantitative land evaluation and crop modelling for dominant cropping systems in major agro-ecological sub-regions (AESRs) representing rice–wheat cropping system in the Indo-Gangetic Plains (IGP) and deep-rooted crops in the black soil regions (BSR). To assess the impact of landuse change, threshold land quality indicator values are used. A modified AESR map for agricultural landuse planning is generated for effective land-use planning

Soil information system: use and potentials in humid and semi-arid tropics

The articles presented in this special section emanated from the researches of consortium members of the National Agricultural Innovative Project (NAIP, Component 4) of the Indian Council of Agricultural Research (ICAR), New Delhi. These researches have helped develop a soil information system (SIS). In view of the changing scenario all over the world, the need of the hour is to get assistance from a host of researchers specialized in soils, crops, geology, geography and information technology to make proper use of the datasets. Equipped with the essential knowledge of data storage and retrieval for management recommendations, these experts should be able to address the issues of land degradation, biodiversity, food security, climate change and ultimately arrive at an appropriate agricultural land-use planning. Moreover, as the natural resource information is an essential prerequisite for monitoring and predicting global environmental change with special reference to climate and land use options, the SIS needs to be a dynamic exercise to accommodate temporal datasets, so that subsequently it should result in the evolution of the soil information technology. The database developed through this NAIP would serve as an example of the usefulness of the Consortium and the research initiative of ICAR involving experts from different fields to find out the potentials of the soils of humid and semi-arid bioclimatic systems of the country

Ichthyosis Linearis Circumflexa

A 4 year old female child presented with ichthyosiform erythroderma. She had few serpiginous ichthyotic patches on her face. The case is presented for its rarity

Generalized benign acanthosis nigricans in an infant

The generalized form of acanthosis nigricans, especially in infants, is extremely rare. Herein we report a 1-year-old female child who developed generalized acanthosis nigricans without any evidence of internal malignancy or endocrine disorder. This case is being reported for its rarity