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  1. Article ; Online: Mitochondrial hyperactivity as a potential therapeutic target in Parkinson’s disease

    Danielle E. Mor / Coleen T. Murphy

    Translational Medicine of Aging, Vol 4, Iss , Pp 117-

    2020  Volume 120

    Abstract: Mitochondrial dysfunction is thought to contribute to neurodegeneration in Parkinson’s disease (PD), yet the cellular events that lead to mitochondrial disruption remain unclear. Post-mortem studies of PD patient brains and the use of complex I ... ...

    Abstract Mitochondrial dysfunction is thought to contribute to neurodegeneration in Parkinson’s disease (PD), yet the cellular events that lead to mitochondrial disruption remain unclear. Post-mortem studies of PD patient brains and the use of complex I inhibitors to model the disease previously suggested a reduction in mitochondrial activity as a causative factor in PD, but this may represent an endpoint in the disease process. In our recent studies, we identified a novel link between branched-chain amino acid metabolism and PD, and uncovered mitochondrial hyperactivity as a potential alternative mechanism of PD pathogenesis. Increased mitochondrial activity may occur in a subset of PD patients, or may be a more common early event that precedes the ultimate loss of mitochondrial function. Therefore, it may be that any imbalance in mitochondrial activity, either increased or decreased, could cause a loss of mitochondrial homeostasis that leads to disease. An effective therapeutic strategy may be to target specific imbalances in activity at selective stages of PD or in specific patients, with any efforts to reduce mitochondrial activity constituting a surprising new avenue for PD treatment.
    Keywords Parkinson’s disease ; Hyperactive mitochondria ; Mitochondrial homeostasis ; Branched-chain amino acid metabolism ; Medicine ; R
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher KeAi Communications Co., Ltd.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: High-throughput behavioral screen in C. elegans reveals Parkinson’s disease drug candidates

    Salman Sohrabi / Danielle E. Mor / Rachel Kaletsky / William Keyes / Coleen T. Murphy

    Communications Biology, Vol 4, Iss 1, Pp 1-

    2021  Volume 9

    Abstract: Salman Sohrabi et al. develop an automated, high-throughput assay to study spasm-like curling behavior in C. elegans, which is related to motor control symptoms in Parkinson’s disease. They apply this screening approach to identify four candidate drugs ... ...

    Abstract Salman Sohrabi et al. develop an automated, high-throughput assay to study spasm-like curling behavior in C. elegans, which is related to motor control symptoms in Parkinson’s disease. They apply this screening approach to identify four candidate drugs for potential late-in-life interventions for Parkinson’s disease.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: GAIT-GM integrative cross-omics analyses reveal cholinergic defects in a C. elegans model of Parkinson’s disease

    Lauren M. McIntyre / Francisco Huertas / Alison M. Morse / Rachel Kaletsky / Coleen T. Murphy / Vrinda Kalia / Gary W. Miller / Olexander Moskalenko / Ana Conesa / Danielle E. Mor

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 9

    Abstract: Abstract Parkinson’s disease (PD) is a disabling neurodegenerative disorder in which multiple cell types, including dopaminergic and cholinergic neurons, are affected. The mechanisms of neurodegeneration in PD are not fully understood, limiting the ... ...

    Abstract Abstract Parkinson’s disease (PD) is a disabling neurodegenerative disorder in which multiple cell types, including dopaminergic and cholinergic neurons, are affected. The mechanisms of neurodegeneration in PD are not fully understood, limiting the development of therapies directed at disease-relevant molecular targets. C. elegans is a genetically tractable model system that can be used to disentangle disease mechanisms in complex diseases such as PD. Such mechanisms can be studied combining high-throughput molecular profiling technologies such as transcriptomics and metabolomics. However, the integrative analysis of multi-omics data in order to unravel disease mechanisms is a challenging task without advanced bioinformatics training. Galaxy, a widely-used resource for enabling bioinformatics analysis by the broad scientific community, has poor representation of multi-omics integration pipelines. We present the integrative analysis of gene expression and metabolite levels of a C. elegans PD model using GAIT-GM, a new Galaxy tool for multi-omics data analysis. Using GAIT-GM, we discovered an association between branched-chain amino acid metabolism and cholinergic neurons in the C. elegans PD model. An independent follow-up experiment uncovered cholinergic neurodegeneration in the C. elegans model that is consistent with cholinergic cell loss observed in PD. GAIT-GM is an easy to use Galaxy-based tool for generating novel testable hypotheses of disease mechanisms involving gene-metabolite relationships.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2022-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: CXCL12-mediated guidance of migrating embryonic stem cell-derived neural progenitors transplanted into the hippocampus.

    Nathaniel W Hartman / Joseph E Carpentino / Kristi LaMonica / Danielle E Mor / Janice R Naegele / Laura Grabel

    PLoS ONE, Vol 5, Iss 12, p e

    2010  Volume 15856

    Abstract: Stem cell therapies for neurodegenerative disorders require accurate delivery of the transplanted cells to the sites of damage. Numerous studies have established that fluid injections to the hippocampus can induce lesions in the dentate gyrus (DG) that ... ...

    Abstract Stem cell therapies for neurodegenerative disorders require accurate delivery of the transplanted cells to the sites of damage. Numerous studies have established that fluid injections to the hippocampus can induce lesions in the dentate gyrus (DG) that lead to cell death within the upper blade. Using a mouse model of temporal lobe epilepsy, we previously observed that embryonic stem cell-derived neural progenitors (ESNPs) survive and differentiate within the granule cell layer after stereotaxic delivery to the DG, replacing the endogenous cells of the upper blade. To investigate the mechanisms for ESNP migration and repair in the DG, we examined the role of the chemokine CXCL12 in mice subjected to kainic acid-induced seizures. We now show that ESNPs transplanted into the DG show extensive migration through the upper blade, along the septotemporal axis of the hippocampus. Seizures upregulate CXCL12 and infusion of the CXCR4 antagonist AMD3100 by osmotic minipump attenuated ESNP migration. We also demonstrate that seizures promote the differentiation of transplanted ESNPs toward neuronal rather than astrocyte fates. These findings suggest that ESNPs transplanted into the adult rodent hippocampus migrate in response to cytokine-mediated signals.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2010-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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