Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin

Tain, Luke S; Chowdhury, Ruhena B.; Tao, Ran; Plun‐Favreau, Hélène; Moisoi, Nicoleta; Martins, L. Miguel; Downward, Julian; Whitworth, Alexander J.; Tapon, Nicolas

doi:10.1038/cdd.2009.23

Cited by 81 publications

(72 citation statements)

References 31 publications

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“…We cannot, however, rule out the possibility that DJ-1 selectively rescues a target downstream of pink1 pathway that is responsible for the effects on thoracic mitochondria. It is interesting that Omi/HtrA2 has also been suggested to partially rescue pink1 mutants in Drosophila in a pathway that is similarly independent of parkin (35).…”

Section: Discussionmentioning

confidence: 99%

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

Hao

Giasson

Bonini

2010

Proc. Natl. Acad. Sci. U.S.A.

243

217

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Mutations or deletions in PARKIN/PARK2, PINK1/PARK6, and DJ-1/ PARK7 lead to autosomal recessive parkinsonism. In Drosophila, deletions in parkin and pink1 result in swollen and dysfunctional mitochondria in energy-demanding tissues. The relationship between DJ-1 and mitochondria, however, remains unclear. We now report that Drosophila and mouse mutants in DJ-1 show compromised mitochondrial function with age. Flies deleted for DJ-1 manifest similar defects as pink1 and parkin mutants: male sterility, shortened lifespan, and reduced climbing ability. We further found poorly coupled mitochondria in vitro and reduced ATP levels in fly and mouse DJ-1 mutants. Surprisingly, up-regulation of DJ-1 can ameliorate pink1, but not parkin, mutants in Drosophila; cysteine C104 (analogous to C106 in human) is critical for this rescue, implicating the oxidative functions of DJ-1 in this property. These results suggest that DJ-1 is important for proper mitochondrial function and acts downstream of, or in parallel to, pink1. These findings link DJ-1, pink1, and parkin to mitochondrial integrity and provide the foundation for therapeutics that link bioenergetics and parkinsonism.parkin | Parkinson's disease | oxidative stress | Drosophila P arkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disease. Clinically, it is characterized by resting tremor, rigidity, bradykinesia, gait abnormality, and slow movement (1, 2). PD patients show severe dopaminergic neuron loss, resulting in a decrease of striatal dopamine levels responsible for the motor features (3, 4). Age is the most potent risk factor for PD, but other contributing factors include exposure to environmental toxins like paraquat and rotenone. Although predominantly idiopathic, genetic mutations account for ≈10% of cases (5). Studies of genes responsible for familial parkinsonism/PD are yielding critical insight into mechanisms shared by sporadic and familial disease.Mutations in DJ-1/PARK7, PINK1/PARK6, and PARKIN/PARK2 lead to autosomal recessive parkinsonism. Properties of DJ-1 suggest that it may be at a compelling intersection for several risk factors in PD, including genetics, oxidative stress, environmental factors, and age. First, DJ-1 gene mutations lead to early-onset autosomal recessive parkinsonism (6). Second, the DJ-1 protein is sensitive to oxidative stress and may act as a redox-responsive molecular chaperone that can prevent protein misfolding (7). Third, tolerance toward paraquat in animals is mediated, in part, through modifications of DJ-1 protein (8). Finally, age induces the same modifications of the DJ-1 protein as environmental toxins (8). Mice mutant for DJ-1 show dopamine reuptake dysfunction (9) and have increased sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) (10). Two DJ-1 orthologs (DJ-1a and DJ-1b) exist in Drosophila, and when deleted, flies have decreased climbing ability (11) and increased sensitivity to H 2 O 2 , paraquat, and rotenone (12). Taken to...

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Section: Discussionmentioning

confidence: 99%

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

Hao

Giasson

Bonini

2010

Proc. Natl. Acad. Sci. U.S.A.

243

217

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“…It is released when the outer mitochondrial membrane is permeabilized in response to stress that leads to inhibition of the inhibitor of apoptosis protein DIAP1, as shown in S2 cells. However, others have shown that HtrA2 is not necessary for apoptosis in vivo, as there is a normal apoptotic response to gamma radiation in wing imaginal discs in HtrA2 mutants (Tain et al 2009). HtrA2 mutants are viable, but they show male sterility and reduced stress resistance and longevity (Yun et al 2008;Tain et al 2009).…”

Section: Discussionmentioning

confidence: 99%

A Link Between Impaired Purine Nucleotide Synthesis and Apoptosis in Drosophila melanogaster

Holland¹,

Lipsett²,

Clark

2011

Genetics

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The biosynthetic pathways and multiple functions of purine nucleotides are well known. However, the pathways that respond to alterations in purine nucleotide synthesis in vivo in an animal model organism have not been identified. We examined the effects of inhibiting purine de novo synthesis in vivo and in cultured cells of Drosophila melanogaster. The purine de novo synthesis gene ade2 encodes phosphoribosylformylglycinamidine synthase (EC 6.3.5.3). An ade2 deletion, generated by P-element transposon excision, causes lethality in early pupal development, with darkening, or necrosis, of leg and wing imaginal disc tissue upon disc eversion. Together with analysis of a previously isolated weaker allele, ade2 4 , and an allele of the Prat gene, which encodes an enzyme for the first step in the pathway, we determined that the lethal arrest and imaginal disc phenotypes involve apoptosis. A transgene expressing the baculovirus caspase inhibitor p35, which suppresses apoptosis caused by other stresses such as DNA damage, suppresses both the imaginal disc tissue darkening and the pupal lethality of all three purine de novo synthesis mutants. Furthermore, we showed the presence of apoptosis at the cellular level in both ade2 and Prat mutants by detecting TUNEL-positive nuclei in wing imaginal discs. Purine de novo synthesis inhibition was also examined in tissue culture by ade2 RNA interference followed by analysis of genome-wide changes in transcript levels. Among the upregulated genes was HtrA2, which encodes an apoptosis effector and is thus a candidate for initiating apoptosis in response to purine depletion.

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“…Rhomboid-7 may also cleave the mitochondrial targeting motif of PINK1, enabling PINK1 activity not only in the mitochondria, but also in the cytosol. Tain et al identified Omi/HtrA2 as a possible regulator of the PINK1-Parkin pathway, acting downstream of PINK1 in Drosophila (Tain et al, 2009). However, another study shows that Omi/HtrA2 does not play a role in the pathway (Yun et al, 2008).…”

Section: Disease Models and Mechanisms Dmmmentioning

confidence: 99%

Mitochondrial dysfunction and Parkinson’s disease genes: insights from Drosophila

Park

Kim

Chung

2009

Disease Models &Amp; Mechanisms

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Parkinson’s disease (PD), one of the most common neurodegenerative disorders worldwide, currently lacks a cure. Although most PD cases occur sporadically, studies from rare genetic mutations give significant insights into addressing the pathological mechanism of not only familial PD, but also sporadic PD. Recent PD research focuses on generating genetic mutant animal models that recapitulate the features of human PD patients. Significant advances in PD research have resulted from studying Drosophila mutants of several identified PD-associated genes because they show strikingly visible phenotypes. In particular, previous studies with the Drosophila mutants parkin and PINK1, which are two common causative genes among PD familial forms, have suggested strongly that mitochondrial dysfunction is the prominent cause for the PD pathogenesis and that these two PD genes are in a common pathway, with Parkin downstream of PINK1. Recent genetic studies have revealed that the PINK1-Parkin pathway is involved in regulating the mitochondrial remodeling process. In addition, PINK1 was recently found to regulate the localization of Parkin through direct phosphorylation. Here, we briefly review these new and exciting findings in Drosophila PD models and discuss how using these models can further advance PD studies.

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Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin

Cited by 81 publications

References 31 publications

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function

A Link Between Impaired Purine Nucleotide Synthesis and Apoptosis in Drosophila melanogaster

Mitochondrial dysfunction and Parkinson’s disease genes: insights from Drosophila

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