Biology subjects

Mor, D.

Publications and source records attributed to Mor, D..

6 recordsLinked to original sources

bioRxiv2026

Monoaminergic changes are associated with impaired neurogenesis along the longitudinal axis of the hippocampus in ageing and dementia

Neurogenesis persists in the adult human hippocampus and is thought to support memory and emotional regulation. Both normal ageing and Parkinson disease dementia (PDD) are associated with reduced hippocampal neurogenesis, but why this occurs and how this might change across the across the hippocampal axis remains unclear. Here, we quantified the expression of genes regulating neurogenesis from stem cell production to neuron maturation and examined their relationship with monoaminergic activity throughout the post-mortem hippocampus in young and aged individuals, as well as in individuals with PDD. DCX and MKI67 expression were markedly reduced in PDD cases throughout the hippocampus, while GFAP and GFAP{delta} were elevated in aged control individuals but not in PDD. Dopamine and serotonin levels were unchanged but reduced levels of the dopamine metabolite DOPAC, and increased levels of the serotonin metabolite 5-HIAA, were present across the hippocampal axis in PDD. Hierarchical regression analysis identified DOPAC and 5-HIAA as significant predictors of DCX and MKI67 expression independent of diagnostic group. Coupling between stem cell markers and proliferative output was preserved in the hippocampus of young controls but was absent in aged controls and in PDD. These data suggest changes in monoaminergic systems are linked to stage-specific deficits in neuronal proliferation and maturation, identifying a potential mechanistic bridge to cognitive decline in PDD.

neuroscience↗

bioRxiv2025

Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model

Wild-type superoxide dismutase 1 (disSOD1) protein misfolding and deposition is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subsequent reduced copper binding to SOD1, is a key factor driving the development of this pathology, suggesting brain copper supplementation may constitute an effective means of preventing its formation. We evaluated the potential of the blood-brain-barrier-permeable copper delivery drug, CuATSM, to attenuate the misfolding and deposition of wild-type disSOD1, and associated neuron death, in a novel mouse model that expresses this pathology. Using proteomic and elemental mass spectrometry, together with biochemical and histological workflows, we demonstrated copper supplementation corrects altered post-translational modifications on soluble SOD1 and improves the enzymatic activity of the protein in the brains of these animals. These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. These data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder.

neuroscience↗

bioRxiv2024

Impaired maturation of wild-type superoxide dismutase 1 associated with neurodegeneration in Parkinson disease brain and a novel murine model

Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health, are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder. We then engineered brain copper deficiency and upregulated SOD1 protein levels in a novel mouse strain, termed the SOCK mouse, to verify their involvement in the development of Parkinson-like wild-type SOD1 pathology and their impact on dopamine neuron health. Soluble SOD1 protein in the degenerating Parkinson disease SNc exhibited altered post-translational modifications, which may underlie changes to the enzymatic activity and aggregation of the protein in this region. These include decreased copper binding, dysregulation of physiological glycosylation, and atypical oxidation and glycation of key SOD1 amino acid residues. We demonstrated that the biochemical profile introduced in SOCK mice promotes the same post-translational modifications and the development of Parkinson-like wild-type SOD1 pathology in the midbrain and cortex. This pathology accumulates progressively with age and is accompanied by nigrostriatal degeneration and dysfunction, which occur in the absence of -synuclein deposition. These mice do not exhibit weight loss nor spinal cord motor neuron degeneration, distinguishing them from transgenic mutant SOD1 mouse models. This study provides the first in vivo evidence that mismetallation and altered post-translational modifications precipitates wild-type SOD1 misfolding, dysfunction and deposition in the Parkinson disease brain, which may contribute to SNc dopamine neuron degeneration. Our data position this pathology as a novel drug target for this disorder, with a particular focus on therapies capable of correcting alterations to SOD1 post-translational modifications.

neuroscience↗

bioRxiv2024

Neurovascular unit adjustments following chronic distress explain motivational deficits in mice

BackgroundThe neurovascular unit (NVU) represents the structural and functional relationship between the neural tissue and the blood. Neurovascular dysfunction has been highlighted in neuropsychiatric afflictions, but whether it is a cause or a consequence of the pathology remains to be elucidated. Thus, to elucidate the role of the NVU on the emergence of emotional-cognitive dysfunction, it is necessary to study how its individual components associate. This study therefore aims at investigating whether the development of depressive-related loss of motivation is grounded on NVU adjustments impacting the permeability of the blood-brain barrier (BBB) and in particular, of the structural scaffolding of microvessels. MethodsAdult male C57BL/6jRj mice chronically treated with corticosterone (CORT) and showing severe motivational deficits in an operant progressive ratio (PR) schedule of reinforcement task, presented altered neural activation assessed through FosB expression in key brain regions involved in motivational processing (anterior insular cortex, basolateral amygdala, bed nucleus of the stria terminalis and ventral tegmental area). We evaluated NVU modifications through immunofluorescence staining targeting specific markers of microglia (IBA-1), endothelial tight junctions (ZO-1) and astrocytes (GFAP). The effect of chronic CORT administration on mice BBB permeability was evaluated through in vivo perfusion of fluorescent 40 kDa Dextran. ResultsOur results highlight that where sustained neuronal activation failed, NVU modifications predict behavioural deficits in CORT-treated animals. Notably, our analyses show that NVU modifications within the ventral tegmental area are essential to understand effort-based related behavioural performance in mice, and most particularly, that the key element of microvessels tight junctions ZO-1 plays a pivotal role on motivation-related behavioural output. ConclusionsOur results confirm a direct role of neurovascular adaptations on emotional and cognitive behavioural performance in mice, and therefore place the NVU in a key position in the research of the biological substrate at the origin of neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Whole-body positive synchronization pattern of metabolic transcriptomes

Understanding the relationship between transcriptomes in the entire body is crucial for comprehending health and disease. To achieve this, we have developed a framework that allows us to measure the general coordination pattern of functionally similar transcriptomes at a whole-body scale. Our approach employs meta-network level analysis to determine the interconnectivity level of metabolic co-expression modules throughout the body as opposed to randomly selected modules. We utilize dimensionality reduction of co-expression modules, inter-tissue connectivity, and clique community analysis. We applied our methodology to 19 distinct human tissues obtained from the GTEx project and detected 40/52 metabolic co-expression modules out of 609/652 cross-tissue generated modules in Cohort 1 and 2 respectively. We detected that the ratio of positive to negative inter-tissue co-expression of metabolic modules was significantly higher than control. We further validated these results for an additional cohort. Moreover, to detect a global concurrent synchronization pattern we performed graph theoretical analysis, specifically a clique community analysis of metabolic transcriptomes showing a significantly larger inter-tissue metabolic transcriptome community that control with a significantly higher connectivity for each metabolic module within the community. Additionally, we performed gene-level validation of our results. In summary, our findings reveal a significant global synchronization pattern of metabolic modules throughout the body. Our framework can be further used for other type of transcriptomes and serve as a measure detecting change in this global coordination pattern across conditions.

systems biology↗

bioRxiv2020

Astroglia in lateral habenula is essential for antidepressant efficacy of light

Successful antidepressant (AD) treatments are still difficult to achieve. Recently, bright light stimulation (BLS) was shown effective in non-seasonal depression but its mode of action remains elusive. We demonstrate here, using a new mouse model of depression resistant to ADs including ketamine, that chemogenetic activation of lateral habenula (LHb) astroglia prevented the potentiating effect of BLS on the AD response. Additionally, the beneficial action of BLS was associated with upregulation of a specific part of the prefrontal cortex opioid system. These results show that improved behavioral outcome produced by BLS requires habenular astroglia and endogenous opioids as crucial buffer systems.

neuroscience↗