Loss-of-function analysis suggests that omi/htra2 is not an essential component of the pink1/parkin pathway in vivo

Yun, Jina, Cao, Joseph H., Dodson, Mark W., Clark, Ira E., Kapahi, Pankaj, Chowdhury, Ruhena B. and Guo, Ming 2008. Loss-of-function analysis suggests that omi/htra2 is not an essential component of the pink1/parkin pathway in vivo. Journal of Neuroscience 28 (53) , pp. 14500-14510. 10.1523/JNEUROSCI.5141-08.2008

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Abstract

Recently, a mutation in the mitochondrial protease Omi/HtrA2, G399S, was found in sporadic Parkinson's disease (PD) patients, leading to the designation of Omi/HtrA2 as PD locus 13 (PARK13). G399S reportedly results in reduced Omi protease activity. In vitro studies have suggested that Omi/HtrA2 acts downstream of PINK1, mutations in which mediate recessive forms of PD. We, as well as other, have previously shown that the Drosophila homologs of the familial PD genes, PINK1 (PARK6) and PARKIN (PARK2), function in a common genetic pathway to regulate mitochondrial integrity and dynamics. Whether Omi/HtrA2 regulates mitochondrial integrity and whether it acts downstream of PINK1 in vivo remain to be explored. Here, we show that Omi/HtrA2 null mutants in Drosophila, in contrast to pink1 or parkin null mutants, do not show mitochondrial morphological defects. Extensive genetic interaction studies do not provide support for models in which Omi/HtrA2 functions in the same genetic pathway as pink1, or carries out partially redundant functions with pink1, at least with respect to regulation of mitochondrial integrity and dynamics. Furthermore, Omi/HtrA2 G399S retains significant, if not full, function of Omi/HtrA2, compared with expression of protease-compromised versions of the protein. In light of recent findings showing that G399S can be found at comparable frequencies in PD patients and healthy controls, we do not favor a hypothesis in which Omi/HtrA2 plays an essential role in PD pathogenesis, at least with respect to regulation of mitochondrial integrity in the pink1/parkin pathway.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Uncontrolled Keywords:	Parkinson's disease; mitochondrial protease; Omi/HtrA2; Pink1; genetic interactions; Drosophila
Additional Information:	Pdf uploaded in accordance with publisher's policy at http://www.jneurosci.org/site/misc/ifa_policies.xhtml#copyright (accessed 27/02/2014).
Publisher:	Society for Neuroscience
ISSN:	0270-6474
Date of First Compliant Deposit:	30 March 2016
Last Modified:	10 May 2023 15:02
URI:	https://orca.cardiff.ac.uk/id/eprint/28871

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