Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2.

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5.

Miniaturised gap sensor using fibre optic Fabry-Pérot interferometry for structural health monitoring.

A miniaturised structural health monitoring device has been developed capable of measuring the absolute distance between close parallel surfaces using Fabry-Pérot interferometry with nm-scale sensitivity. This is achieved by fabricating turning mirrors on two opposite cores of a multi-core fibre to produce a probe with dimensions limited only be the fibre diameter. Two fabrication processes have been investigated: Focused ion beam milling, which has resulted in a sensor measurement accuracy, sensitivity and range of ±0.

Loss of CRMP2 O-GlcNAcylation leads to reduced novel object recognition performance in mice.

O-GlcNAcylation is an abundant post-translational modification in the nervous system, linked to both neurodevelopmental and neurodegenerative disease. However, the mechanistic links between these phenotypes and site-specific O-GlcNAcylation remain largely unexplored. Here, we show that Ser517 O-GlcNAcylation of the microtubule-binding protein Collapsin Response Mediator Protein-2 (CRMP2) increases with age.

CTIP2-Regulated Reduction in PKA-Dependent DARPP32 Phosphorylation in Human Medium Spiny Neurons: Implications for Huntington Disease.

The mechanisms underlying the selective degeneration of medium spiny neurons (MSNs) in Huntington disease (HD) remain largely unknown. CTIP2, a transcription factor expressed by all MSNs, is implicated in HD pathogenesis because of its interactions with mutant huntingtin. Here, we report a key role for CTIP2 in protein phosphorylation via governing protein kinase A (PKA) signaling in human striatal neurons.

Community Treatment Orders and Other Forms of Mandatory Outpatient Treatment.

This position paper has been substantially revised by the Canadian Psychiatric Association's Professional Standards and Practice Committee and approved for republication by the CPA's Board of Directors on July 26, 2018. The original position paper was first approved by the Board of Directors on January 25, 2003. It was subsequently reviewed and approved for republication with minor revisions on June 2, 2009.

Phosphorylation of Parkin at serine 65 is essential for its activation .

Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in mammals remains unknown.

Motor Assessment in Huntington's Disease Mice.

Motor deficits are a characteristic consequence of striatal damage, whether induced by experimental lesions, or in genetic models of Huntington's disease involving polyglutamine expansion in the huntingtin protein. With the growing power of genetic models and genetic tools for analysis, mice are increasingly the animal model of choice, and objective quantitative measures of motor performance are in demand for experimental analysis of disease pathophysiology, progression, and treatment. We present methodological protocols for six of the most common tests of motor function-ranging from spontaneous activity, locomotor coordination, balance, and skilled limb use-that are simple, effective, efficient, and widely used for motor assessment in Huntington's disease research in experimental mice.

The Effect of Tissue Preparation and Donor Age on Striatal Graft Morphology in the Mouse.

Huntington's disease (HD) is a progressive neurodegenerative disease in which striatal medium spiny neurons (MSNs) are lost. Neuronal replacement therapies aim to replace MSNs through striatal transplantation of donor MSN progenitors, which successfully improve HD-like deficits in rat HD models and have provided functional improvement in patients. Transplants in mouse models of HD are more variable and have lower cell survival than equivalent rat grafts, yet mice constitute the majority of transgenic HD models.

Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand.

Dysregulated mitophagy has been linked to Parkinson's disease (PD) due to the role of PTEN-induced kinase 1 (PINK1) in mediating depolarization-induced mitophagy in vitro. Elegant mouse reporters have revealed the pervasive nature of basal mitophagy in vivo, yet the role of PINK1 and tissue metabolic context remains unknown. Using mito-QC, we investigated the contribution of PINK1 to mitophagy in metabolically active tissues.

Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.Htt model of Huntington's disease.

We investigated the appearance and progression of disease-relevant signs in the B6.Htt mouse, a genetically precise model of the mutation that causes Huntington's disease (HD). We find that B6.

Correction: Huntingtin Subcellular Localisation Is Regulated by Kinase Signalling Activity in the StHdhQ111 Model of HD.

[This corrects the article DOI: 10.1371/journal.pone.

A Longitudinal Operant Assessment of Cognitive and Behavioural Changes in the HdhQ111 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is characterised by motor symptoms which are often preceded by cognitive and behavioural changes, that can significantly contribute to disease burden for people living with HD. Numerous knock-in mouse models of HD are currently available for scientific research. However, before their use, they must be behaviourally characterised to determine their suitability in recapitulating the symptoms of the human condition.

A Longitudinal Motor Characterisation of the HdhQ111 Mouse Model of Huntington's Disease.

Background: Huntington's disease (HD) is a rare, incurable neurodegenerative disorder caused by a CAG trinucleotide expansion with the first exon of the huntingtin gene. Numerous knock-in mouse models are currently available for modelling HD. However, before their use in scientific research, these models must be characterised to determine their face and predictive validity as models of the disease and their reliability in recapitulating HD symptoms.

Comparison of mHTT Antibodies in Huntington's Disease Mouse Models Reveal Specific Binding Profiles and Steady-State Ubiquitin Levels with Disease Development.

Huntington's disease (HD) cellular pathology is characterised by the aggregation of mutant huntingtin (mHTT) protein into inclusion bodies. The present paper compared the sensitivity of five widely used mHTT antibodies (S830; MW8; EM48; 1C2; ubiquitin) against mice from five commonly used HD mouse models (R6/1; YAC128; HdhQ92; B6 HdhQ150; B6 x129/Ola HdhQ150) at two ages to determine: the most sensitive antibodies for each model; whether mHTT antibody binding differed depending on aggregation stage (diffuse versus frank inclusion); the role of ubiquitin during aggregation as the ubiquitin proteosome system has been implicated in disease development. The models demonstrated unique profiles of antibody binding even when the models varied only by background strain (HdhQ150).

Cognitive training modifies disease symptoms in a mouse model of Huntington's disease.

Huntington's disease (HD) is an incurable neurodegenerative disorder which causes a triad of motor, cognitive and psychiatric disturbances. Cognitive disruptions are a core feature of the disease, which significantly affect daily activities and quality of life, therefore cognitive training interventions present an exciting therapeutic intervention possibility for HD. We aimed to determine if specific cognitive training, in an operant task of attention, modifies the subsequent behavioural and neuropathological phenotype of the Hdh(Q111) mouse model of HD.

Similar striatal gene expression profiles in the striatum of the YAC128 and HdhQ150 mouse models of Huntington's disease are not reflected in mutant Huntingtin inclusion prevalence.

Background: The YAC128 model of Huntington's disease (HD) shows substantial deficits in motor, learning and memory tasks and alterations in its transcriptional profile. We examined the changes in the transcriptional profile in the YAC128 mouse model of HD at 6, 12 and 18 months and compared these with those seen in other models and human HD caudate.

Results: Differential gene expression by genotype showed that genes related to neuronal function, projection outgrowth and cell adhesion were altered in expression.

Huntingtin Subcellular Localisation Is Regulated by Kinase Signalling Activity in the StHdhQ111 Model of HD.

Huntington's disease is a neurodegenerative disorder characterised primarily by motor abnormalities, and is caused by an expanded polyglutamine repeat in the huntingtin protein. Huntingtin dynamically shuttles between subcellular compartments, and the mutant huntingtin protein is mislocalised to cell nuclei, where it may interfere with nuclear functions, such as transcription. However, the mechanism by which mislocalisation of mutant huntingtin occurs is currently unknown.

Optimising Golgi-Cox staining for use with perfusion-fixed brain tissue validated in the zQ175 mouse model of Huntington's disease.

Background: The Golgi-Cox stain is an established method for characterising neuron cell morphology. The method highlights neurite processes of stained cells allowing the complexity of dendritic branching to be measured.

New Methods: Conventional rapid Golgi and Golgi-Cox methods all require fresh impregnation in unfixed brain blocks.

In Vivo MRI Evidence that Neuropathology is Attenuated by Cognitive Enrichment in the Yac128 Huntington's Disease Mouse Model.

Background: Environmental enrichment has been shown to improve symptoms and reduce neuropathology in mouse models of Huntington's disease (HD); however results are limited to ex vivo techniques with associated shortcomings. In-vivo magnetic resonance imaging (MRI) can overcome some of the shortcomings and is applied for the first time here to assess the effect of a cognitive intervention in a mouse model of HD.

Objectives: We aimed to investigate whether in-vivo high-field MRI can detect a disease-modifying effect in tissue macrostructure following a cognitive enrichment regime.

The utilisation of operant delayed matching and non-matching to position for probing cognitive flexibility and working memory in mouse models of Huntington's disease.

Background: Operant behavioural testing provides a highly sensitive and automated method of exploring the behavioural deficits seen in rodent models of neurodegenerative diseases, including Huntington's disease (HD). The delayed matching to position (DMTP) and delayed non-matching to position (DNMTP) tasks probe spatial learning and working memory and when applied serially they can be used to measure reversal learning, which has been shown to be an early symptom of executive dysfunction in HD.

New Method: The DMTP and DNMTP tasks were conducted in two configurations of operant apparatus; the conventional 9-hole operant apparatus, and a Skinner-like operant apparatus, to compare, contrast and optimise the DMTP and DNMTP operant protocols for use in mice.

Towards the discrimination of carboxylates by hydrogen-bond donor anion receptors.

The binding constants (log Kass ) of small synthetic receptor molecules based on indolocarbazole, carbazole, indole, urea and some others, as well as their combinations were measured for small carboxylate anions of different basicity, hydrophilicity and steric demands, that is, trimethylacetate, acetate, benzoate and lactate, in 0.5 % H2 O/[D6 ]DMSO by using the relative NMR-based measurement method. As a result, four separate binding affinity scales (ladders) including thirty-eight receptors were obtained with the scales anchored to indolocarbazole.

Identification of novel alternative splicing events in the huntingtin gene and assessment of the functional consequences using structural protein homology modelling.

Huntington's disease (HD) is an inherited progressive neurodegenerative disorder caused by a pathological CAG trinucleotide repeat expansion in the large multi-exon gene, huntingtin (HTT). Although multiple pathogenic mechanisms have been proposed for HD, there is increasing interest in the RNA processing of the HTT gene. In mammals, most multi-exon genes are alternatively spliced; however, few alternative transcripts have been described for HTT.

Mouse Models of Huntington's Disease.

In this review, we explore the similarities and differences in the behavioural neurobiology found in the mouse models of Huntington's disease (HD) and the human disease state. The review is organised with a comparative focus on the functional domains of motor control, cognition and behavioural disturbance (akin to psychiatric disturbance in people) and how our knowledge of the underlying physiological changes that are manifest in the HD mouse lines correspond to those seen in the HD clinical population. The review is framed in terms of functional circuitry and neurotransmitter systems and how abnormalities in these systems impact on the behavioural readouts across the mouse lines and how these may correspond to the deficits observed in people.