Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by ...the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington's disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin's gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington's disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington's disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington's disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington's disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington's disease.
Loss of cellular homeostasis has been implicated in the etiology of several neurodegenerative diseases (NDs). However, the molecular mechanisms that underlie this loss remain poorly understood on a ...systems level in each case. Here, using a novel computational approach to integrate dimensional RNA-seq and in vivo neuron survival data, we map the temporal dynamics of homeostatic and pathogenic responses in four striatal cell types of Huntington's disease (HD) model mice. This map shows that most pathogenic responses are mitigated and most homeostatic responses are decreased over time, suggesting that neuronal death in HD is primarily driven by the loss of homeostatic responses. Moreover, different cell types may lose similar homeostatic processes, for example, endosome biogenesis and mitochondrial quality control in
-expressing neurons and astrocytes. HD relevance is validated by human stem cell, genome-wide association study, and post-mortem brain data. These findings provide a new paradigm and framework for therapeutic discovery in HD and other NDs.
Abstract
Motivation
Huntington’s disease (HD) may evolve through gene deregulation. However, the impact of gene deregulation on the dynamics of genetic cooperativity in HD remains poorly understood. ...Here, we built a multi-layer network model of temporal dynamics of genetic cooperativity in the brain of HD knock-in mice (allelic series of Hdh mice). To enhance biological precision and gene prioritization, we integrated three complementary families of source networks, all inferred from the same RNA-seq time series data in Hdh mice, into weighted-edge networks where an edge recapitulates path-length variation across source-networks and age-points.
Results
Weighted edge networks identify two consecutive waves of tight genetic cooperativity enriched in deregulated genes (critical phases), pre-symptomatically in the cortex, implicating neurotransmission, and symptomatically in the striatum, implicating cell survival (e.g. Hipk4) intertwined with cell proliferation (e.g. Scn4b) and cellular senescence (e.g. Cdkn2a products) responses. Top striatal weighted edges are enriched in modulators of defective behavior in invertebrate models of HD pathogenesis, validating their relevance to neuronal dysfunction in vivo. Collectively, these findings reveal highly dynamic temporal features of genetic cooperativity in the brain of Hdh mice where a 2-step logic highlights the importance of cellular maintenance and senescence in the striatum of symptomatic mice, providing highly prioritized targets.
Availability and implementation
Weighted edge network analysis (WENA) data and source codes for performing spectral decomposition of the signal (SDS) and WENA analysis, both written using Python, are available at http://www.broca.inserm.fr/HD-WENA/.
Supplementary information
Supplementary data are available at Bioinformatics online.
Neurodegenerative diseases (ND) have been linked to the critical process in aging—cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we ...show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16INK4a, a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16INK4a expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16INK4a promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3‐ETS2‐p16INK4a axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.
Increasingly pronounced senescence features develop in human Huntington's disease (HD) neural stem cells and striatal neurons, including the increase of p16INK4a. The FOXO3/ß‐catenin complex can oppose these cellular senescence features via transcriptional reprogramming in a Ryk‐dependent manner, antagonizing p16INK4a expression via the repression of the transcriptional modulator ETS2. The HD brain neural lineage may thus face a continuous senescence process.
MicroRNA (miRNA) regulation is associated with several diseases, including neurodegenerative diseases. Several approaches can be used for modeling miRNA regulation. However, their precision may be ...limited for analyzing multidimensional data. Here, we addressed this question by integrating shape analysis and feature selection into miRAMINT, a methodology that we used for analyzing multidimensional RNA-seq and proteomic data from a knock-in mouse model (Hdh mice) of Huntington's disease (HD), a disease caused by CAG repeat expansion in huntingtin (htt). This dataset covers 6 CAG repeat alleles and 3 age points in the striatum and cortex of Hdh mice.
Remarkably, compared to previous analyzes of this multidimensional dataset, the miRAMINT approach retained only 31 explanatory striatal miRNA-mRNA pairs that are precisely associated with the shape of CAG repeat dependence over time, among which 5 pairs with a strong change of target expression levels. Several of these pairs were previously associated with neuronal homeostasis or HD pathogenesis, or both. Such miRNA-mRNA pairs were not detected in cortex.
These data suggest that miRNA regulation has a limited global role in HD while providing accurately-selected miRNA-target pairs to study how the brain may compute molecular responses to HD over time. These data also provide a methodological framework for researchers to explore how shape analysis can enhance multidimensional data analytics in biology and disease.
Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we ...show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16
, a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of FOXO3, a major cell survival factor able to repress cell senescence, antagonizing p16
expression via the FOXO3 repression of the transcriptional modulator ETS2. Additionally, p16
promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the FOXO3-ETS2-p16
axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.
The specific role of size scale, surface capping, and aspect ratio of zinc oxide (ZnO) particles on toxicity toward prokaryotic and eukaryotic cells was investigated. ZnO nano and microparticles of ...controlled size and morphology were synthesized by wet chemical methods. Cytotoxicity toward mammalian cells was studied using a human osteoblast cancer cell line and antibacterial activity using Gram-negative bacteria (
Escherichia coli)
as well as using Gram-positive bacteria (
Staphylococcus aureus)
. Scanning electron microscopy (SEM) was conducted to characterize any visual features of the biocidal action of ZnO. We observed that antibacterial activity increased with reduction in particle size. Toxicity toward the human cancer cell line was considerably higher than previously observed by other researchers on the corresponding primary cells, suggesting selective toxicity of the ZnO to cancer cells. Surface capping was also found to profoundly influence the toxicity of ZnO nanoparticles toward the cancer cell line, with the toxicity of starch-capped ZnO being the lowest. Our results are found to be consistent with a membrane-related mechanism for nanoparticle toxicity toward microbes.
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