21 research outputs found
Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model
Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an
aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative
correlation between the number of CAG repeats and the age of disease onset is established, additional
factors may contribute to the high heterogeneity of the complex manifestation of symptoms
among patients. This variability is also observed in mouse models, even under controlled genetic
and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain
in search of potential correlates between pathological motor/cognitive phenotypical traits and
transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated
across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum),
exhibited tissue-specific correlations with particular phenotypical traits that were attributable to
the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum
and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation
associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores,
especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b).
However, we also observed transcripts associated with relatively better outcomes, such as Nfya
(CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development,
apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be
related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to
the highly heterogeneous population of HD patients
Intracranial V. cholerae Sialidase Protects against Excitotoxic Neurodegeneration
Converging evidence shows that GD3 ganglioside is a critical effector in a number of apoptotic pathways, and GM1 ganglioside has neuroprotective and noötropic properties. Targeted deletion of GD3 synthase (GD3S) eliminates GD3 and increases GM1 levels. Primary neurons from GD3S−/− mice are resistant to neurotoxicity induced by amyloid-β or hyperhomocysteinemia, and when GD3S is eliminated in the APP/PSEN1 double-transgenic model of Alzheimer's disease the plaque-associated oxidative stress and inflammatory response are absent. To date, no small-molecule inhibitor of GD3S exists. In the present study we used sialidase from Vibrio cholerae (VCS) to produce a brain ganglioside profile that approximates that of GD3S deletion. VCS hydrolyzes GD1a and complex b-series gangliosides to GM1, and the apoptogenic GD3 is degraded. VCS was infused by osmotic minipump into the dorsal third ventricle in mice over a 4-week period. Sensorimotor behaviors, anxiety, and cognition were unaffected in VCS-treated mice. To determine whether VCS was neuroprotective in vivo, we injected kainic acid on the 25th day of infusion to induce status epilepticus. Kainic acid induced a robust lesion of the CA3 hippocampal subfield in aCSF-treated controls. In contrast, all hippocampal regions in VCS-treated mice were largely intact. VCS did not protect against seizures. These results demonstrate that strategic degradation of complex gangliosides and GD3 can be used to achieve neuroprotection without adversely affecting behavior
Biofluid Biomarkers in Huntington's Disease
Huntington's disease (HD) is a chronic progressive neurodegenerative condition where new markers of disease progression are needed. So far no disease-modifying interventions have been found, and few interventions have been proven to alleviate symptoms. This may be partially explained by the lack of reliable indicators of disease severity, progression, and phenotype.Biofluid biomarkers may bring advantages in addition to clinical measures, such as reliability, reproducibility, price, accuracy, and direct quantification of pathobiological processes at the molecular level; and in addition to empowering clinical trials, they have the potential to generate useful hypotheses for new drug development.In this chapter we review biofluid biomarker reports in HD, emphasizing those we feel are likely to be closest to clinical applicability
Protein oxidative modifications: new mass spectrometry approaches to detection in biological samples
This paper looks at new mass spectronomy approaches to detection in biological samples
Transmitter content, origins and connections of axons in the spinal cord that possess the serotonin (5-hydroxytryptamine) 3 receptor
Characterisation of immune cell function in fragment and full-length Huntington's disease mouse models
Inflammation is a growing area of research in neurodegeneration. In Huntington's disease (HD), a fatal inherited neurodegenerative disease caused by a CAG-repeat expansion in the gene encoding huntingtin, patients have increased plasma levels of inflammatory cytokines and circulating monocytes that are hyper-responsive to immune stimuli. Several mouse models of HD also show elevated plasma levels of inflammatory cytokines. To further determine the degree to which these models recapitulate observations in HD patients, we evaluated various myeloid cell populations from different HD mouse models to determine whether they are similarly hyper-responsive, as well as measuring other aspects of myeloid cell function. Myeloid cells from each of the three mouse models studied, R6/2, HdhQ150 knock-in and YAC128, showed increased cytokine production when stimulated. However, bone marrow CD11b<sup>+</sup> cells did not show the same hyper-responsive phenotype as spleen and blood cells. Furthermore, macrophages isolated from R6/2 mice show increased levels of phagocytosis, similar to findings in HD patients. Taken together, these results show significant promise for these mouse models to be used to study targeting innate immune pathways identified in human cells, thereby helping to understand the role the peripheral immune system plays in HD progressio
Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum
Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimer's disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimer's disease progression. Here, we used an in vitro assay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimer's disease or remained cognitively stable. Mild cognitive impairment to Alzheimer's disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of 'baseline' cellular readouts together with education level were able to predict Alzheimer's disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.Adult hippocampal neurogenesis is altered early in the course of Alzheimer's disease. Maruszak et al. show that serum from patients with MCI who do versus do not progress to Alzheimer's disease differentially affects the fate of hippocampal stem cells in vitro, suggesting that this assay could help predict disease progression
Acute-phase proteins in relation to neuropsychiatric symptoms and use of psychotropic medication in Huntington׳s disease
Neurological Motor Disorder