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Aims: Metabolic dysfunction is involved in modulating the disease process in Huntington disease (HD) but the underlying mechanisms are not known. The aim of this study was to investigate if the metabolic regulators sirtuins are affected in HD. Methods: Quantitative real‐time polymerase chain reactions were used to assess levels of SIRT1‐3 and downstream targets in post mortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin (HTT) using recombinant adeno‐associated viral vectors in mice. Results: We show that mRNA levels of the metabolic regulator SIRT1 are increased in the striatum and the cerebral cortex but not in the less affected cerebellum in post mortem HD brains. Levels of SIRT2 are only increased in the striatum and SIRT3 is not affected in HD. Interestingly, mRNA levels of SIRT1 are selectively increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets and reduced mRNA levels of orexin (hypocretin), prodynorphin and melanin‐concentrating hormone (MCH) in the LHA and of brain‐derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant HTT suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes in SIRT1 require more widespread expression of mutant HTT. Conclusions: We show that SIRT1 expression is increased in HD‐affected brain regions and that metabolic pathways are altered in the HD hypothalamus. [ABSTRACT FROM AUTHOR]

The most common cause of autosomal recessive familial Parkinson's disease (PD) are mutations in the PRKN/PARK2 gene encoding an E3 ubiquitin protein-ligase PARKIN. We report the generation of an iPSC cell line from the fibroblasts of a male PD patient carrying a common missense variant in exon 7 (p.Arg275Trp), and a 133 kb deletion encompassing exon 8, using transiently-present Sendai virus. The established line displays typical human primed iPSC morphology and expression of pluripotency-associated markers, normal karyotype without SNP array-detectable copy number variations and can give rise to derivatives of all three embryonic germ layers. We envisage the usefulness of this iPSC line, carrying a common and well-studied missense mutation in the RING1 domain of the PARKIN protein, for the elucidation of PARKIN-dependent mechanisms of PD using in vitro and in vivo models. [ABSTRACT FROM AUTHOR]

Neuropathological and cell culture studies suggest that tau and α-synuclein pathologies may promote each other. To study the relevance and functional implications of these findings in vivo, we transduced hippocampal neurons of wild-type or human A30P α-synuclein transgenic mice with wild-type or P301S mutated human tau using an adeno-associated virus vector. Green fluorescent protein transduction was used as a control. We assessed spontaneous exploratory activity, anxiety and spatial learning and memory 11 weeks after the transduction and perfused the mice for histology. The transduced tau was mainly found in axon terminals and largely restricted within the hippocampi. In addition, neurons around the injection site showed cytoplasmic staining for human tau in both wild-type and A30P mice. Of these tau-positive neurons, 44% in A30P mice but only 3% in wild-type mice receiving human wild-type tau transduction formed paired helical filament-1 (PHF-1)-positive cytoplasmic densities. In contrast, only 1% of tau-positive neurons were also PHF-1 positive after transduction with P301S tau in mice of either genotype. Transduction of P301S tau reduced swimming speed but otherwise tau transduction had no significant behavioral consequences. Cytoplasmic PHF-1 densities were associated with poor spatial memory in wild-type mice but slightly improved memory in A30P mice, indicating that also tau hyperphosphorylation does not necessarily compromise neural functions. These data demonstrate that α-synuclein promotes tau hyperphosphorylation depending on the amino acids on the 301 site. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Grafts of foetal ventral mesencephalon, used in cell replacement therapy for Parkinson's disease, are known to contain a mix of dopamine neuronal subtypes including the A9 neurons of the substantia nigra and the A10 neurons of the ventral tegmental area. However, the relative importance of these subtypes for functional repair of the brain affected by Parkinson's disease has not been studied thoroughly. Here, we report results from a series of grafting experiments where the anatomical and functional properties of grafts either selectively lacking in A9 neurons, or with a typical A9/A10 composition were compared. The results show that the A9 component of intrastriatal grafts is of critical importance for recovery in tests on motor performance, in a rodent model of Parkinson's disease. Analysis at the histological level indicates that this is likely to be due to the unique ability of A9 neurons to innervate and functionally activate their target structure, the dorsolateral region of the host striatum. The findings highlight dopamine neuronal subtype composition as a potentially important parameter to monitor in order to understand the variable nature of functional outcome better in transplantation studies. Furthermore, the results have interesting implications for current efforts in this field to generate well-characterized and standardized preparations of transplantable dopamine neuronal progenitors from stem cells. [ABSTRACT FROM AUTHOR]

Background Psychiatric symptoms and metabolic changes occur early in Huntington's disease (HD) and may be a result of hypothalamic dysfunction. The hypothalamus has emerged as an important site of pathology, but a causative relationship between hypothalamic dysfunction and non-motor features in HD remain to be established. Cre-recombinase (cre) mediated excision allows inactivation of mutant huntingtin (htt) in the BACHD mouse and it is therefore a useful tool to study structure to functional relationships. Aims The aim of this study was to investigate whether the BACHD mouse displays psychiatric and metabolic disturbances. As hypothalamus regulates metabolism, we also tested whether inactivation of mutant htt in the hypothalamus could prevent the development of metabolic alterations. Methods The psychiatric profile was assessed with Porsolt forced swim test and elevated plus maze. The metabolic phenotype was determined with DEXA, indirect calorimetry, glucose and insulin tolerance tests and ELISA. Results We found that BACHD mice developed both depressive-like and anxiety-like behaviours at an early age. They also displayed enhanced accumulation of fat, impaired glucose tolerance as well as insulin and leptin resistance. The increase in body weight was due to increased appetite. Inactivation of mutant htt in the hypothalamus in young BACHD mice using adeno associated viral vectors expressing cre prevented the development of the metabolic phenotype. Conclusions Our data demonstrate that BACHD mice display early depressive and anxiety-like behaviours as well as a metabolic phenotype. The metabolic disturbances in this model are caused by hypothalamic dysfunction. [ABSTRACT FROM PUBLISHER]

Background The homeostatic control of emotions and metabolism is disturbed early in Huntington's disease (HD), which may be due to changes in hypothalamic function. Previous studies have identified a loss of orexin (hypocretin) neurons in the lateral hypothalamus in HD patients. There has been only limited assessment of other hypothalamic regions in HD. Aims The aim of the study was to assess the neuropeptide expressing hypothalamic neurons known to regulate metabolism and emotion in HD patients compared with healthy controls. Methods Hypothalamic serial sections from HD (n=6) and controls (n=4) cases were processed for cresyl violet, Luxol fast blue and immunohistochemistry. Quantification of total cell numbers was performed using unbiased stereology. Results Substantial differences exist in peptide expression of different neuronal populations in HD hypothalamus compared with controls. In addition to loss of orexin expressing neurons, both oxytocin and vasopressin expressing neurons were decreased. The number of cocaine and amphetamine regulated transcript (CART) expressing neurons was increased. The increased expression of CART in the hypothalamus is consistent with a previous study showing increased CART levels in CSF from HD patients. There was no difference in the numbers of neuropeptide Y expressing neurons. Conclusions These results show significant and specific alterations in the peptide expression of hypothalamic neurons known to regulate metabolism and emotion. These changes may be important for the development of the psychiatric symptoms and metabolic disturbances characterising HD, and may provide potential targets for therapeutic interventions. [ABSTRACT FROM PUBLISHER]

Background Non-motor features of Huntington's disease (HD) include metabolic changes such as increased appetite, insulin resistance and changes in body weight. As mutant huntingtin (htt) is ubiquitously expressed in HD as well as in most animal models that recapitulate these features, it has not been possible to determine the underlying pathology. Metabolism is regulated by the hypothalamus and previous reports have suggested hypothalamic dysfunction in HD including loss of orexin (hypocretin), a neuropeptide involved in the control of sleep, metabolism and emotion. Aims The aim of this study was to test if selective expression of mutant htt in the hypothalamus would lead to metabolic disturbances. Methods We used adeno associated viral vectors as tools to deliver the first 853 amino acid fragment of either the wild-type or mutant form of the htt gene in the hypothalamus of mice. Results We detected formation of htt inclusions and ubiquitinated aggregates in the absence of general cell loss, gliosis or microglia activation in the hypothalamus. Interestingly, selective hypothalamic expression of mutant htt, but not the wild-type form of htt expressed at a similar level, caused severe metabolic disturbances including glucose intolerance, insulin and leptin resistance as well as a significant increase in body fat and body weight. These changes were accompanied by loss of orexin. Conclusions This study provides evidence for a causative relationship between the effects of mutant htt in the hypothalamus and the development of metabolic disturbances. [ABSTRACT FROM PUBLISHER]