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000265796 041__ $$aEnglish
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000265796 1001_ $$00000-0002-2005-4546$$aGrossmann, Dajana$$b0
000265796 245__ $$aMitochondria-Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1-PD or PRKN-PD Neurons.
000265796 260__ $$aNew York, NY$$bWiley$$c2023
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000265796 520__ $$aIt 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.
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000265796 650_2 $$2MeSH$$aHumans
000265796 650_2 $$2MeSH$$aParkinson Disease: pathology
000265796 650_2 $$2MeSH$$aCalcium: metabolism
000265796 650_2 $$2MeSH$$aThapsigargin: metabolism
000265796 650_2 $$2MeSH$$aMitochondria: pathology
000265796 650_2 $$2MeSH$$aDopaminergic Neurons: metabolism
000265796 650_2 $$2MeSH$$aProtein Kinases: genetics
000265796 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: genetics
000265796 650_2 $$2MeSH$$aEndoplasmic Reticulum: metabolism
000265796 650_2 $$2MeSH$$aHomeostasis
000265796 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aPTEN-induced putative kinase
000265796 650_7 $$2Other$$aPINK1
000265796 650_7 $$2Other$$aParkin
000265796 650_7 $$2Other$$aParkinson's disease
000265796 650_7 $$2Other$$acalcium
000265796 650_7 $$2Other$$amitochondria-ER contact sites
000265796 650_7 $$0SY7Q814VUP$$2NLM Chemicals$$aCalcium
000265796 650_7 $$067526-95-8$$2NLM Chemicals$$aThapsigargin
000265796 650_7 $$0EC 2.7.-$$2NLM Chemicals$$aProtein Kinases
000265796 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aUbiquitin-Protein Ligases
000265796 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aparkin protein
000265796 7001_ $$aMalburg, Nina$$b1
000265796 7001_ $$00000-0003-3155-5300$$aGlaß, Hannes$$b2
000265796 7001_ $$aWeeren, Veronika$$b3
000265796 7001_ $$aSondermann, Verena$$b4
000265796 7001_ $$aPfeiffer, Julia F$$b5
000265796 7001_ $$aPetters, Janine$$b6
000265796 7001_ $$00000-0002-8061-5798$$aLukas, Jan$$b7
000265796 7001_ $$00000-0002-3496-7194$$aSeibler, Philip$$b8
000265796 7001_ $$00000-0003-2102-3431$$aKlein, Christine$$b9
000265796 7001_ $$00000-0002-4179-2994$$aGrünewald, Anne$$b10
000265796 7001_ $$0P:(DE-2719)2811732$$aHermann, Andreas$$b11$$eLast author
000265796 773__ $$0PERI:(DE-600)2041249-6$$a10.1002/mds.29525$$gVol. 38, no. 10, p. 1822 - 1836$$n10$$p1822 - 1836$$tMovement disorders$$v38$$x0885-3185$$y2023
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