Abstract
High temperature requirement A2 (HtrA2/Omi) is a mitochondrial protease that exhibits proapoptotic and cell-protective properties and has been linked to Parkinson's disease (PD). Impaired mitochondrial function is a common trait in PD patients, and is likely to play a significant role in pathogenesis of parkinsonism, but the molecular mechanisms remain poorly understood. Genetic studies in Drosophila have provided valuable insight into the function of other PD-linked genes, in particular PINK1 and parkin, and their role in maintaining mitochondrial integrity. Recently, HtrA2 was shown to be phosphorylated in a PINK1-dependent manner, suggesting it might act in the PINK1 pathway. Here, we describe the characterization of mutations in Drosophila HtrA2, and genetic analysis of its function with PINK1 and parkin. Interestingly, we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis. In addition, we found HtrA2 mutants share some phenotypic similarities with parkin and PINK1 mutants, suggesting that it may function in maintaining mitochondrial integrity. Our genetic interaction studies, including analysis of double-mutant combinations and epistasis experiments, suggest HtrA2 acts downstream of PINK1 but in a pathway parallel to Parkin.
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Abbreviations
- HtrA2:
-
high temperature requirement A2
- PD:
-
Parkinson's disease
- PINK1:
-
PTEN induced putative kinase 1
- IAP:
-
inhibitor of apoptosis protein
- mnd2 :
-
motor neuron degeneration
- SAPK:
-
stress-activated protein kinase
- MTS:
-
mitochondrial targeting sequence
- TM:
-
transmembrane domain
- PDZ:
-
postsynaptic density protein (PSD95), disc large, zonula occludens-1
- H2-Opt:
-
HtrA2 optimal
- mRpL11:
-
mitochondrial ribosomal protein-like 11
- STS:
-
staurosporine
- UV:
-
ultraviolet
- IFM:
-
indirect flight muscle
- WT:
-
wild type
- PARL:
-
presenilin-associated rhomboid-like
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Acknowledgements
We thank J Chung and the Bloomington Drosophila Stock Center for fly stocks, T Gilbank, S Murray and F Earl for fly transgenics, G Kelly for help with statistical analysis, C Gray for help with movies and K Klupsch for comments on the article. We are grateful to M Guo for sharing data before publication. AW and LT acknowledge the Department of Biomedical Science, Centre for Electron Microscopy for assistance, and the Light Microscopy Facility is supported by the Wellcome Trust (Grant No. GR077544AIA). AW is funded by the Parkinson's Disease Society (G-4063, G-0713) and the Wellcome Trust (081987). The MRC Centre for Developmental and Biomedical Genetics is supported by Grant G070091. LMM is supported by the MRC (UK). Work in the Tapon and Downward laboratories is supported by Cancer Research UK. HPF is supported by the MRC Grant G0700183.
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Tain, L., Chowdhury, R., Tao, R. et al. Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differ 16, 1118–1125 (2009). https://doi.org/10.1038/cdd.2009.23
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DOI: https://doi.org/10.1038/cdd.2009.23
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