19 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
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
Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors
Major depressive disorder (MDD) is increasingly viewed as interplay of environmental stressors and genetic predisposition, and recent data suggest that the disease affects not only the brain, but the entire body. As a result, we aimed at determining whether patients with major depression have aberrant molecular responses to stress in peripheral tissues. We examined the effects of two metabolic stressors, galactose (GAL) or reduced lipids (RL), on the transcriptome and miRNome of human fibroblasts from 16 pairs of patients with MDD and matched healthy controls (CNTR). Our results demonstrate that both MDD and CNTR fibroblasts had a robust molecular response to GAL and RL challenges. Most importantly, a significant part (messenger RNAs (mRNAs): 26-33%; microRNAs (miRNAs): 81-90%) of the molecular response was only observed in MDD, but not in CNTR fibroblasts. The applied metabolic challenges uncovered mRNA and miRNA signatures, identifying responses to each stressor characteristic for the MDD fibroblasts. The distinct responses of MDD fibroblasts to GAL and RL revealed an aberrant engagement of molecular pathways, such as apoptosis, regulation of cell cycle, cell migration, metabolic control and energy production. In conclusion, the metabolic challenges evoked by GAL or RL in dermal fibroblasts exposed adaptive dysfunctions on mRNA and miRNA levels that are characteristic for MDD. This finding underscores the need to challenge biological systems to bring out disease-specific deficits, which otherwise might remain hidden under resting conditions
Cross-talk between neural stem cells and immune cells: the key to better brain repair?
Systemic or intracerebral delivery of neural stem and progenitor cells (NSPCs) and activation of endogenous NSPCs hold much promise as potential treatments for diseases in the human CNS. Recent studies have shed new light on the interaction between the NSPCs and cells belonging to the innate and adaptive arms of the immune system. According to these studies, the immune cells can be both beneficial and detrimental for cell genesis from grafted and endogenous NSPCs in the CNS, and the NSPCs exert their beneficial effects not only by cell replacement but also by immunomodulation and trophic support. The cross-talk between immune cells and NSPCs and their progeny seems to determine both the efficacy of endogenous regenerative responses and the mechanism of action as well as the fate and functional integration of grafted NSPCs. Better understanding of the dialog between NSPCs and innate and adaptive immune cells is crucial for further development of effective strategies for CNS repair