دورية أكاديمية
Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.
| العنوان: | Mitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons. |
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| المؤلفون: | Grossmann, Dajana, Malburg, Nina, Grünewald, Anne, Hermann, Andreas, Glaß, Hannes, Weeren, Veronika, Sondermann, Verena, Pfeiffer, Julia F, Petters, Janine, Lukas, Jan, Seibler, Philip, Klein, Christine |
| المصدر: | Movement disorders 38(10), 1822 - 1836 (2023). doi:10.1002/mds.29525 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | info:eu-repo/classification/ddc/610, Humans, Parkinson Disease: pathology, Calcium: metabolism, Thapsigargin: metabolism, Mitochondria: pathology, Dopaminergic Neurons: metabolism, Protein Kinases: genetics, Ubiquitin-Protein Ligases: genetics, Endoplasmic Reticulum: metabolism, Homeostasis, PTEN-induced putative kinase, PINK1, Parkin, Parkinson's disease, calcium, mitochondria-ER contact sites, Thapsigargin, Protein Kinases, Ubiquitin-Protein Ligases, parkin protein |
| جغرافية الموضوع: | DE |
| الوصف: | It is generally believed that the pathogenesis of PINK1/parkin-related Parkinson's disease (PD) is due to a disturbance in mitochondrial quality control. However, recent studies have found that PINK1 and Parkin play a significant role in mitochondrial calcium homeostasis and are involved in the regulation of mitochondria-endoplasmic reticulum contact sites (MERCSs).The aim of our study was to perform an in-depth analysis of the role of MERCSs and impaired calcium homeostasis in PINK1/Parkin-linked PD.In our study, we used induced pluripotent stem cell-derived dopaminergic neurons from patients with PD with loss-of-function mutations in PINK1 or PRKN. We employed a split-GFP-based contact site sensor in combination with the calcium-sensitive dye Rhod-2 AM and applied Airyscan live-cell super-resolution microscopy to determine how MERCSs are involved in the regulation of mitochondrial calcium homeostasis.Our results showed that thapsigargin-induced calcium stress leads to an increase of the abundance of narrow MERCSs in wild-type neurons. Intriguingly, calcium levels at the MERCSs remained stable, whereas the increased net calcium influx resulted in elevated mitochondrial calcium levels. However, PINK1-PD or PRKN-PD neurons showed an increased abundance of MERCSs at baseline, accompanied by an inability to further increase MERCSs upon thapsigargin-induced calcium stress. Consequently, calcium distribution at MERCSs and within mitochondria was disrupted.Our results demonstrated how the endoplasmic reticulum and mitochondria work together to cope with calcium stress in wild-type neurons. In addition, our results suggests that PRKN deficiency affects the dynamics and composition of MERCSs differently from PINK1 deficiency, resulting in differentially affected calcium homeostasis. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/pmid:37449534; info:eu-repo/semantics/altIdentifier/issn/1531-8257; info:eu-repo/semantics/altIdentifier/issn/0885-3185; https://pub.dzne.de/record/265796Test; https://pub.dzne.de/search?p=id:%22DZNE-2023-01040%22Test |
| الإتاحة: | https://doi.org/10.1002/mds.29525Test https://pub.dzne.de/record/265796Test https://pub.dzne.de/search?p=id:%22DZNE-2023-01040%22Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.92476B7 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |