Neuroprotective Role of the Reaper-Related Serine Protease HtrA2/Omi Revealed by Targeted Deletion in Mice

Abstract

The serine protease HtrA2/Omi is released from the mitochondrial intermembrane space following apoptotic stimuli. Once in the cytosol, HtrA2/Omi has been implicated in promoting cell death by binding to inhibitor of apoptosis proteins (IAPs) via its amino-terminal Reaper-related motif, thus inducing caspase activity, and also in mediating caspase-independent death through its own protease activity. We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25. These animals, or cells derived from them, show no evidence of reduced rates of cell death but on the contrary suffer loss of a population of neurons in the striatum, resulting in a neurodegenerative disorder with a parkinsonian phenotype that leads to death of the mice around 30 days after birth. The phenotype of these mice suggests that it is the protease function of this protein and not its IAP binding motif that is critical. This conclusion is reinforced by the finding that simultaneous deletion of the other major IAP binding protein, Smac/DIABLO, does not obviously alter the phenotype of HtrA2/Omi knockout mice or cells derived from them. Mammalian HtrA2/Omi is therefore likely to function in vivo in a manner similar to that of its bacterial homologues DegS and DegP, which are involved in protection against cell stress, and not like the proapoptotic Reaper family proteins in Drosophila melanogaster.

Caspase function in programmed cell death

“…137 HtrA2 KO animals die around 30 days after birth owing to a neurodegenerative disorder, but cells derived from these animals fail to show any resistance to apoptosis. 138 Combined deficiency of HtrA2 and SMAC leads to a phenotype similar to HtrA2 deficiency alone, suggesting that these two proteins are not compensating for each other. 138 Xiap KO mice are also phenotypically normal and fail to show any defects in apoptosis.…”

“…138 Combined deficiency of HtrA2 and SMAC leads to a phenotype similar to HtrA2 deficiency alone, suggesting that these two proteins are not compensating for each other. 138 Xiap KO mice are also phenotypically normal and fail to show any defects in apoptosis. 139 Although it is possible that in the absence of XIAP, SMAC and HtrA2, other yet unknown mechanisms can compensate for these proteins, the KO phenotypes suggest that these proteins are themselves not essential for developmental PCD.…”

Mitochondrial dysfunction in Parkinson's disease

“…The G399S mutation results in reduced serineprotease activity Omi/HTRA2 knockout mice display a parkinsonian phenotype that includes rigidity but additional features that include ataxia muscle wasting and premature death. 67 …”

Omi/HtrA2 is a positive regulator of autophagy that facilitates the degradation of mutant proteins involved in neurodegenerative diseases

“…These mice died within 30 days after birth, similarly to mnd2 mice. 10 Furthermore, many other neurodegenerative disease proteins, such as presenilin-1 4,11 or amyloid precursor protein, 12 were reported to be associated with Omi.…”