Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila

Fernandes, Caroline S.; Rao, Yong

doi:10.1186/1756-6606-4-17

Cited by 32 publications

(26 citation statements)

References 49 publications

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“…28 Supporting a potential role for of OPA1 in PINK1/parkindependent mitochondrial abnormalities, OPA1 has been identified as a PD-interacting gene in genome-wide screen analyses for modifiers of PD genes in Drosophila Pink1/park mutants. 29 In our study, mitochondrial structural abnormalities linked to complex I inhibition were not associated with significant mitochondrial fragmentation. Although earlier reports have indicated the occurrence of mitochondrial fission following intoxication by parkinsonian neurotoxins, [30][31][32] recent studies failed to detect mitochondrial fragmentation in MPP þ -treated murine mesencephalic dopaminergic primary neurons.…”

Section: Discussionmentioning

confidence: 59%

Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency

et al. 2012

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Mitochondrial complex I dysfunction has long been associated with Parkinson's disease (PD). Recent evidence suggests that mitochondrial involvement in PD may extend beyond a sole respiratory deficit and also include perturbations in mitochondrial fusion/fission or ultrastructure. Whether and how alterations in mitochondrial dynamics may relate to the known complex I defects in PD is unclear. Optic atrophy 1 (OPA1), a dynamin-related GTPase of the inner mitochondrial membrane, participates in mitochondrial fusion and apoptotic mitochondrial cristae remodeling. Here we show that complex I inhibition by parkinsonian neurotoxins leads to an oxidative-dependent disruption of OPA1 oligomeric complexes that normally keep mitochondrial cristae junctions tight. As a consequence, affected mitochondria exhibit major structural abnormalities, including cristae disintegration, loss of matrix density and swelling. These changes are not accompanied by mitochondrial fission but a mobilization of cytochrome c from cristae to intermembrane space, thereby lowering the threshold for activation of mitochondria-dependent apoptosis by cell death agonists in compromised neurons. All these pathogenic changes, including mitochondrial structural remodeling and dopaminergic neurodegeneration, are abrogated by OPA1 overexpression, both in vitro and in vivo. Our results identify OPA1 as molecular link between complex I deficiency and alterations in mitochondrial dynamics machinery and point to OPA1 as a novel therapeutic target for complex I cytopathies, such as PD.

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Section: Discussionmentioning

confidence: 59%

Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency

et al. 2012

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“…Similar phenotypes have been reported in flies harboring mutations in several known disease-causing genes that impact mitochondrial function. For example, Pink and Parkin mutants display abnormal wing posture, and mtATP6 mutants are bang sensitive (Celotto et al, 2006b; Fernandes and Rao, 2011). Human mutations in Pink/Parkin and mtATP6 are known to cause familial Parkinson’s disease and mitochondrial encephalopathy, respectively (Schapira, 2012).…”

Section: Discussionmentioning

confidence: 99%

SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration

et al. 2014

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SUMMARY Succinate dehydrogenase (SDH) occupies a central place in cellular energy production, linking the tricarboxylic cycle with the electron transport chain. As a result, a subset of cancers and neuromuscular disorders result from mutations affecting any of the four SDH structural subunits or either of two known SDH assembly factors. Herein we characterize a novel evolutionarily conserved SDH assembly factor designated Sdh8/SDHAF4, using yeast, Drosophila, and mammalian cells. Sdh8 interacts specifically with the catalytic Sdh1 subunit in the mitochondrial matrix, facilitating its association with Sdh2 and the subsequent assembly of the SDH holocomplex. These roles for Sdh8 are critical for preventing motility defects and neurodegeneration in Drosophila as well as the excess ROS generated by free Sdh1. These studies provide insights into the mechanisms by which SDH is assembled and raise the possibility that some forms of neuromuscular disease may be associated with mutations that affect this SDH assembly factor.

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“…The unique attributes of Drosophila (robust phenotypes, straightforward genetics providing opportunities for genome-wide genetic screens and drug screens) suggest that Drosophila studies will continue to move the field forward and help identify Animal Models-Drosophila Cite this article as Cold Spring Harb Perspect Med 2012;2:a009944 novel therapies for PD, and potentially other aging-related neurodegenerative disorders. In support of this contention, compounds and a number of genes (either over-or underexpressed, or exogenous) have been identified as suppressors of PINK1 and/or parkin phenotypes in the fly Whitworth et al 2005;Deng et al 2008;Poole et al 2008;Yang et al 2008;Park et al 2009;Tain et al 2009;Hao et al 2010;Imai et al 2010;Liu and Lu 2010;Fernandes and Rao 2011;Saini et al 2011;Koh et al 2012;Vilain et al 2012). Given that defects in mitochondria accumulate in normal aging as well as in PD, identifying multiple ways of activating mitophagy may be generally useful therapeutically in many diseases of aging.…”

Section: Contributions Of Drosophila and Future Directionsmentioning

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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Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila

Cited by 32 publications

References 49 publications

Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency

Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency

SDHAF4 Promotes Mitochondrial Succinate Dehydrogenase Activity and Prevents Neurodegeneration

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

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