Computer simulations predict the impact of neuronal atrophy on the calcium dynamics in Huntington's disease
© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences..
One of the early hallmarks of Huntington's disease (HD) is neuronal cell atrophy, especially in the striatum, underlying motor dysfunction in HD. Here using a computer model, we have predicted the impact of cell shrinkage on calcium dynamics at the cellular level. Our model indicates that as cytosolic volume decreases, the amplitude of calcium transients increases and the endoplasmic reticulum (ER) becomes more leaky due to calcium-induced calcium release and a "toxic" positive feedback mechanism mediated by ryanodine receptors that greatly increases calcium release into the cytosol. The excessive calcium release from ER saturates the calcium buffering capacity of calbindin and forces further accumulation of free calcium in the cytosol and cellular compartments including mitochondria. This leads to imbalance of calcium in both cytosol and ER regions. Excessive calcium accumulation in the cytosol can damage the mitochondria resulting in metabolic dysfunction in the cell consistent with the pathology of HD. Our computational model points toward potential drug targets and can accelerate and greatly help the experimental studies of HD paving the way for treatments of patients suffering from HD.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:3 |
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| Enthalten in: |
PNAS nexus - 3(2024), 1 vom: 09. Jan., Seite pgad443 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sameni, Sara [VerfasserIn] |
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| Links: |
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| Themen: |
Aging |
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| Anmerkungen: |
Date Revised 10.02.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1093/pnasnexus/pgad443 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences. | ||
| 520 | |a One of the early hallmarks of Huntington's disease (HD) is neuronal cell atrophy, especially in the striatum, underlying motor dysfunction in HD. Here using a computer model, we have predicted the impact of cell shrinkage on calcium dynamics at the cellular level. Our model indicates that as cytosolic volume decreases, the amplitude of calcium transients increases and the endoplasmic reticulum (ER) becomes more leaky due to calcium-induced calcium release and a "toxic" positive feedback mechanism mediated by ryanodine receptors that greatly increases calcium release into the cytosol. The excessive calcium release from ER saturates the calcium buffering capacity of calbindin and forces further accumulation of free calcium in the cytosol and cellular compartments including mitochondria. This leads to imbalance of calcium in both cytosol and ER regions. Excessive calcium accumulation in the cytosol can damage the mitochondria resulting in metabolic dysfunction in the cell consistent with the pathology of HD. Our computational model points toward potential drug targets and can accelerate and greatly help the experimental studies of HD paving the way for treatments of patients suffering from HD | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a biomarkers | |
| 650 | 4 | |a calcium metabolism | |
| 650 | 4 | |a computational model | |
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| 700 | 1 | |a Corey-Bloom, Jody |e verfasserin |4 aut | |
| 700 | 1 | |a Sejnowski, Terrence J |e verfasserin |4 aut | |
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