The antioxidant Trolox helps recovery from the familial Parkinson's disease-specific mitochondrial deficits caused by PINK1- and DJ-1-deficiency in dopaminergic neuronal cells

Shim, Jung Hee; Yoon, Seung Hee; Kim, Kyung Hee; Han, Ji Young; Ha, Ji Young; Hyun, Dong Hoon; Paek, Sun Ha; Kang, Un Jung; Zhuang, Xiaoxi; Son, Jin H.

doi:10.1016/j.mito.2011.05.013

Cited by 45 publications

(44 citation statements)

References 42 publications

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“…Second, expression of human PINK1 (Clark et al 2006;Yang et al 2006) or PARKIN in Drosophila suppresses phenotypes caused by loss of function of PINK1 or parkin, respectively, suggesting that the human and fly proteins are functionally conserved. Third, cells from patients and/or mouse knockout models of PINK1 or parkin also show defects in mitochondrial morphology and/or mitochondrial respiration, particularly in complex I activity in a variety of cell types (Greene et al 2003;Muftuoglu et al 2004;Palacino et al 2004;Exner et al 2007;Hoepken et al 2007;Stichel et al 2007;Gautier et al 2008;Poole et al 2008;Wood-Kaczmar et al 2008;Dagda et al 2009;Gegg et al 2009;Morais et al 2009;Sandebring et al 2009;Grünewald et al 2010;Billia et al 2011;Schmidt et al 2011;Shim et al 2011). Fourth, in neurons derived from pluripotent stem cells from PD patients harboring PINK1 mutations, recruitment of Parkin to mitochondria is impaired (Seibler et al 2011).…”

Section: Genetics and Compound Screens Provide Unbiased Methods For Imentioning

confidence: 99%

Drosophila as a Model to Study Mitochondrial Dysfunction in Parkinson's Disease

Guo¹

2012

Cold Spring Harbor Perspectives in Medicine

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Identification of single gene mutations that lead to inherited forms of Parkinson's disease (PD) has provided strong impetus for the use of animal models to study normal functions of these "PD genes" and the cellular defects that occur in the presence of pathogenic PD mutations. Drosophila has emerged as an effective model in PD-related gene studies. Important insights into the cellular basis of PD pathogenesis include the demonstration that two PD genes, PINK1 and parkin, function in a common pathway, with PINK1 positively regulating parkin, to control mitochondrial integrity and maintenance. This is accomplished through regulation of mitochondrial fission/fusion dynamics. Subsequent observations in both fly and mammalian systems showed that these proteins are important for sensing mitochondrial damage and recruiting damaged mitochondria to the quality-control machinery for subsequent removal. Here, I begin by reviewing the opportunities and challenges to understanding PD pathogenesis and developing new therapies. I then review the unique tools and technologies available in Drosophila for studying PD genes. Subsequently, I review lessons that we have learned from studies in Drosophila, emphasizing the PINK1/parkin pathway, as well as studies of DJ-1 and Omi/HtrA2, two additional genes associated with PD implicated in regulation of mitochondrial function. I end by discussing how Drosophila can be used to further probe the functions of PINK1 and parkin, and the regulation of mitochondrial quality more generally. In additional to PD, defects in mitochondrial function are associated with normal aging and with many diseases of aging. Thus, insights gained from the studies of mitochondrial dynamics and quality control in Drosophila are likely to be of general significance. Parkinson's disease (PD) is the second most common neurodegenerative disorder, with a prevalence second only to that of Alzheimer's disease. There is no cure or treatment that can halt disease progression. A primary pathological hallmark of the disease is degeneration of multiple neuronal types including, most notably, dopaminergic neurons in the substantia nigra of the midbrain (Dauer and Przedborski 2003;Shulman et al. 2011). However, pathology of many non-dopaminergic neurons including olfactory and brain stem neurons predates that of DA neurons (Braak et al. 2003). Patients with PD present with characteristic "motor symptoms," such as resting tremor, slowness of movement, rigidity, postural instability, and gait difficulty. Although the mainstay of current medical treatment for PD is dopamine replacement, this is not very satisfying. First, the dopamine replacement only alleviates some of the motor symptoms (does not help gait problems), becomes less effective over time, and is often associated with intolerable side effects. Second, PD patients also present with a combination of non-motor symptoms (Simuni and Sethi 2008) including dementia, which occurs in more than one-third of patients; psychiatric symptoms such as depression, anxiety, and ob...

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Section: Genetics and Compound Screens Provide Unbiased Methods For Imentioning

confidence: 99%

Drosophila as a Model to Study Mitochondrial Dysfunction in Parkinson's Disease

Guo¹

2012

Cold Spring Harbor Perspectives in Medicine

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“…The wild-type dopaminergic neuronal cell line SN4741 and PINK1-null dopaminergic neuronals cells, which were derived from the same transgenic animal lines with the C57BL/6 genetic background (31,34), were cultured at 33°C with 5% CO 2 in RF medium (DMEM (Invitrogen) supplemented with 10% FBS (HyClone), 1% glucose, penicillin (100 units/ml)-streptomycin (100 g/ml) (Invitrogen, catalog no. 15070-063), and L-glutamine (2 mM) (Invitrogen)).…”

Section: Materials-carbonylmentioning

confidence: 99%

“…Isolation of Mitochondria-Mitochondria were prepared as described previously (31,33). Briefly, cells were washed with ice-cold PBS and suspended in 10 mM ice-cold Tris buffer (pH 7.6) with a protease inhibitor mixture.…”

Section: Materials-carbonylmentioning

confidence: 99%

“…PINK1 deficiency leads to mild to severe decreases in mitochondrial complex activities in PD patient-derived fibroblast cultures (26), PINK1-null mice and fruit flies (27)(28)(29)(30) and PINK1-deficient dopaminergic neuronal cells (31) and loss of phosphorylation of complex I subunit NdufA10 at Ser 250 (32). We have demonstrated previously that PINK1 deficiency also results in a mitochondrial complex IV deficit because of reduced expression of the complex IV assembly factor leucinerich pentatricopeptide repeat containing (LRPPRC) and dysregulated NO signaling (33) and that low levels of NO treatment help PINK1-deficient dopaminergic neurons restore the function of their defective PINK1-LRPPRC-Hsp60-complex IV signaling axis (33).…”

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confidence: 99%

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Nitric Oxide Induction of Parkin Translocation in PTEN-induced Putative Kinase 1 (PINK1) Deficiency

Han¹,

Kang²,

Kim³

et al. 2015

Journal of Biological Chemistry

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Background: A novel mechanism underlying mitochondrial translocation of Parkin during mitophagy is uncovered. Results: nNOS plays a significant role in Parkin translocation via interaction with full-length PINK1. Conclusion: Parkin recruitment through the interaction of nNOS with full-length PINK1 occurs during CCCP-induced mitophagy. Significance: Optimum levels of NO are sufficient for triggering the translocation of Parkin, even in the absence of PINK1, suggesting the feasibility of NO-based pharmacotherapy.

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“…The mitochondrial targeted antioxidant MitoQ has been shown to help in preservation of mitochondrial function after glutathione depletion, this drug is currently in a phase II clinical trial for Parkinson's disease (http://www.parkinsons.org.nz/news/protectstudy.asp). The other compounds which have shown promise in ameliorating the mitochondrial www.intechopen.com dysfunction in experimental PD studies include creatine, lanosterol, melatonin, edaravone and trolox (Shim et al, 2011). However further studies are warranted before the clinical use of these drugs.…”

Section: Parkinson's Disease (Pd)mentioning

confidence: 99%