PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death

Gandhi, Sonia; Wood‐Kaczmar, Alison; Yao, Zhi; Plun‐Favreau, Hélène; Deas, Emma; Klupsch, Kristina; Downward, Julian; Latchman, David S.; Tabrizi, Sarah J.; Wood, Nicholas; Duchen, Michael R.; Abramov, Andrey Y.

doi:10.1016/j.molcel.2009.02.013

Cited by 590 publications

(560 citation statements)

References 42 publications

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“…Inhibition of mitochondrial respiration due to reduced substrates from the TCA cycle has been previously shown in the PINK1 model of PD, leading to dopamine-induced cell death (Gandhi et al, 2009;Abramov et al, 2011). This can be prevented either by providing the cells directly with mitochondrial substrates, and also by treating them with the Nrf2 activators sulforaphane or RTA 408, which are able to revert the bioenergetic alterations caused by the lack of substrates for the TCA cycle and prevent the dopamine-induced cell death in this model .…”

Section: Nrf2 Mitochondrial Bioenergetics and Neurodegenerative Disomentioning

confidence: 74%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

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132

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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Section: Nrf2 Mitochondrial Bioenergetics and Neurodegenerative Disomentioning

confidence: 74%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

Self Cite

132

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“…Several studies reported that loss of PINK1 function causes mitochondrial dysfunction (26,30,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Parkin has been reported to compensate for PINK1 deficiency in the fly model, and we, therefore, addressed the question of whether parkin itself plays a role in maintaining mitochondrial integrity.…”

Section: Discussionmentioning

confidence: 99%

Loss of Parkin or PINK1 Function Increases Drp1-dependent Mitochondrial Fragmentation

Lutz¹,

Exner

Fett³

et al. 2009

Journal of Biological Chemistry

356

324

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Loss-of-function mutations in the parkin gene (PARK2) and PINK1 gene (PARK6) are associated with autosomal recessive parkinsonism. PINK1 deficiency was recently linked to mitochondrial pathology in human cells and Drosophila melanogaster, which can be rescued by parkin, suggesting that both genes play a role in maintaining mitochondrial integrity. Here we demonstrate that an acute down-regulation of parkin in human SH-SY5Y cells severely affects mitochondrial morphology and function, a phenotype comparable with that induced by PINK1 deficiency. Alterations in both mitochondrial morphology and ATP production caused by either parkin or PINK1 loss of function could be rescued by the mitochondrial fusion proteins Mfn2 and OPA1 or by a dominant negative mutant of the fission protein Drp1. Both parkin and PINK1 were able to suppress mitochondrial fragmentation induced by Drp1. Moreover, in Drp1-deficient cells the parkin/PINK1 knockdown phenotype did not occur, indicating that mitochondrial alterations observed in parkin-or PINK1-deficient cells are associated with an increase in mitochondrial fission. Notably, mitochondrial fragmentation is an early phenomenon upon PINK1/parkin silencing that also occurs in primary mouse neurons and Drosophila S2 cells. We propose that the discrepant findings in adult flies can be explained by the time of phenotype analysis and suggest that in mammals different strategies may have evolved to cope with dysfunctional mitochondria.Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson disease, starting from the early observation that the complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced acute and irreversible parkinsonism in young drug addicts (for review, see Refs. 1-3). In support of a crucial role of mitochondria in Parkinson disease, several Parkinson diseaseassociated gene products directly or indirectly impinge on mitochondrial integrity (for review, see . A clear link between Parkinson disease genes and mitochondria has recently emerged from studies on PINK1 (PTEN-induced putative kinase 1), a mitochondrial serine/threonine kinase, and parkin, a cytosolic E3 ubiquitin ligase. Drosophila parkin null mutants displayed reduced life span, male sterility, and locomotor defects due to apoptotic flight muscle degeneration (7). The earliest manifestation of muscle degeneration and defective spermatogenesis was mitochondrial pathology, exemplified by swollen mitochondria and disintegrated cristae. Remarkably, Drosophila PINK1 null mutants shared marked phenotypic similarities with parkin mutants, and parkin could compensate for the PINK1 loss-of-function phenotype but not vice versa, leading to the conclusion that PINK1 and parkin function in a common genetic pathway with parkin acting downstream of PINK1 (8 -10). We recently demonstrated that PINK1 deficiency in cultured human cells causes alterations in mitochondrial morphology, which can be rescued by wild type parkin but not by pathogenic parkin mutant...

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“…Fluorescence microscopy was performed using a Zeiss LSM780 confocal microscope system with a 20x objective, using time-series frames with an interval of 2 s. After baseline interval, stimuli diluted in Tyrode's solution were added, including high KCl (30 mM), L-glutamate (1 mM), FCCP and antimycin A (both 1 mM), or thapsigargin (1 mM). Alternatively, increasing doses of calcium (5 mM, 10 mM, 50 mM CaCl 2 ) were added in calciumfree Tyrode's solution (Gandhi et al, 2009). Preincubation with digitonin (0.2 mM) was included for the last three stimuli.…”

Section: Calcium Imagingmentioning

confidence: 99%

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

et al. 2017

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SUMMARYMitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.

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PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death

Cited by 590 publications

References 42 publications

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Loss of Parkin or PINK1 Function Increases Drp1-dependent Mitochondrial Fragmentation

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

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