Loss-of-Function Analysis Suggests ThatOmi/HtrA2Is Not an Essential Component of thepink1/parkinPathwayIn Vivo

Yun, Jina; Cao, Joseph; Dodson, Mark K.; Clark, Ira E.; Kapahi, Pankaj; Chowdhury, Ruhena B.; Guo, Ming

doi:10.1523/jneurosci.5141-08.2008

Cited by 83 publications

(67 citation statements)

References 53 publications

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“…An overexpressionbased genetic interaction is observed between PINK1 and omi/HtrA2 Yun et al 2008). However, in contrast to PINK1 mutants, omi/HtrA2-null mutants have normal mitochondrial morphology in both muscle and testes, and a normal number of dopaminergic neurons (Yun et al 2008). In addition, extensive loss-of-function-based genetic interaction studies fail to provide any in vivo evidence supporting the hypothesis that Omi/HtrA2 functions in the same pathway, either upstream or downstream of PINK1, to either positively or negatively regulate PINK1.…”

Section: Pink1 and Parkin Promote Mitophagymentioning

confidence: 99%

“…In addition, extensive loss-of-function-based genetic interaction studies fail to provide any in vivo evidence supporting the hypothesis that Omi/HtrA2 functions in the same pathway, either upstream or downstream of PINK1, to either positively or negatively regulate PINK1. They also do not provide any clear evidence that Omi/HtrA2 acts in a parallel manner to regulate mitochondrial morphology (Yun et al 2008). These loss-of-function-based analyses are more relevant to PD than are Omi/ HtrA2 overexpression-based analyses, because reported Omi/HtrA2 mutations associated with PD are proposed to represent loss-of-function or dominant-negative mutations (Strauss et al 2005).…”

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confidence: 92%

“…These loss-of-function-based analyses are more relevant to PD than are Omi/ HtrA2 overexpression-based analyses, because reported Omi/HtrA2 mutations associated with PD are proposed to represent loss-of-function or dominant-negative mutations (Strauss et al 2005). In addition, mutant forms of the Drosophila Omi/HtrA2 analogous to the reported disease form in sporadic PD patients, and a mutant lacking a serine thought to be a target for PINK1-dependent phosphorylation (PlunFavreau et al 2007), retain significant, if not full, Omi/HtrA2 function in vivo (Yun et al 2008). Thus, loss-of-function studies strongly suggest that Omi/HtrA2 does not play an essential role in regulating mitochondrial integrity in the PINK1/parkin pathway in Drosophila (Yun et al 2008).…”

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confidence: 99%

“…In addition, mutant forms of the Drosophila Omi/HtrA2 analogous to the reported disease form in sporadic PD patients, and a mutant lacking a serine thought to be a target for PINK1-dependent phosphorylation (PlunFavreau et al 2007), retain significant, if not full, Omi/HtrA2 function in vivo (Yun et al 2008). Thus, loss-of-function studies strongly suggest that Omi/HtrA2 does not play an essential role in regulating mitochondrial integrity in the PINK1/parkin pathway in Drosophila (Yun et al 2008). Recent studies in mice show that neurodegeneration in the Omi/HtrA2 mutant is not rescued by overexpression of parkin in mice (Yoshida et al 2010).…”

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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: Pink1 and Parkin Promote Mitophagymentioning

confidence: 99%

mentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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 same research group also reports mitochondrial protease high temperature requirement A2 (HtrA2/Omi) as a direct binding partner and indirect phosphorylation target of PINK1 (Plun-Favreau et al, 2007). However, Drosophila genetic studies do not indicate that HtrA2 acts in the same pathway as PINK1 (Yun et al, 2008). Moreover, the molecular link between PINK1 and TRAP1 awaits further genetic confirmation using animal models.…”

Section: Other Mitochondrial Partners Of Pink1 In Mitochondrial Protementioning

confidence: 99%

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

Koh

Chung

2012

Molecules and Cells

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Parkinson's disease (PD), the most prevalent neurodegenerative movement disorder, is characterized by an agedependent selective loss of dopaminergic (DA) neurons. Although most PD cases are sporadic, more than 20 responsible genes in familial cases were identified recently. Genetic studies using Drosophila models demonstrate that PINK1, a mitochondrial kinase encoded by a PD-linked gene PINK1, is critical for maintaining mitochondrial function and integrity. This suggests that mitochondrial dysfunction is the main cause of PD pathogenesis. Further genetic and cell biological studies revealed that PINK1 recruits Parkin, an E3 ubiquitin ligase encoded by another PD-linked gene parkin, to mitochondria and regulates the mitochondrial remodeling process via the Parkin-mediated ubiquitination of various mitochondrial proteins. PINK1 also directly phosphorylates the mitochondrial proteins Miro and TRAP1, subsequently inhibiting mitochondrial transport and mitochondrial oxidative damage, respectively. Moreover, recent Drosophila genetic analyses demonstrate that the neuroprotective molecules Sir2 and FOXO specifically complement mitochondrial dysfunction and DA neuron loss in PINK1 null mutants, suggesting that Sir2 and FOXO protect mitochondria and DA neurons downstream of PINK1. Collectively, these recent results suggest that PINK1 plays multiple roles in mitochondrial quality control by regulating its mitochondrial, cytosolic, and nuclear targets.

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In a flurry of PINK, mitochondrial bioenergetics takes a leading role in Parkinson's disease

Murphy

2009

EMBO Mol Med

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For many years research in Parkinson's disease (PD) has linked mitochondrial dysfunction with the characteristic loss of dopaminergic neurons of the substantia nigra, accumulation of cytoplasmic inclusions termed Lewy bodies, and motor dysfunction (Henchcliffe & Beal, 2008). The most compelling connection is that Parkinsonism can be observed in both humans and animals following exposure to inhibitors of complex I of the electron transport chain (Betarbet et al, 2002).

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Loss-of-Function Analysis Suggests ThatOmi/HtrA2Is Not an Essential Component of thepink1/parkinPathwayIn Vivo

Cited by 83 publications

References 53 publications

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

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

PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity

In a flurry of PINK, mitochondrial bioenergetics takes a leading role in Parkinson's disease

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