Abstract
OMI/HTRA2 (high-temperature requirement serine protease A2) is a mitochondrial serine protease involved in several cellular processes, including autophagy, chaperone activity, and apoptosis. Few studies on the role of OMI/HTRA2 in Alzheimer’s disease (AD) are available, but none on its relationship with the cholinergic system and neurotrophic factors as well as other AD-related proteins. In this study, immunohistochemical analyses revealed that AD patients had a higher cytosolic distribution of OMI/HTRA2 protein compared to controls. Quantitative analyses on brain extracts indicated a significant increase in the active form of OMI/HTRA2 in the AD brain. Activated OMI/HTRA2 protein positively correlated with stress-associated read-through acetylcholinesterase activity. In addition, α7 nicotinic acetylcholine receptor gene expression, a receptor also known to be localized on the outer membrane of mitochondria, showed a strong correlation with OMI/HTRA2 gene expression in three different brain regions. Interestingly, the activated OMI/HTRA2 levels also correlated with the activity of the acetylcholine-biosynthesizing enzyme, choline acetyltransferase (ChAT); with levels of the neurotrophic factors, NGF and BDNF; with levels of the soluble fragments of amyloid precursor protein (APP); and with gene expression of the microtubule-associated protein tau in the examined brain regions. Overall, the results demonstrate increased levels of the mitochondrial serine protease OMI/HTRA2, and a coherent pattern of association between the activated form of OMI/HTRA2 and several key proteins involved in AD pathology. In this paper, we propose a new hypothetical model to highlight the importance and needs of further investigation on the role of OMI/HTRA2 in the mitochondrial function and AD.
Highlights
OMI/HTRA2 is a mitochondrial serine protease and member of the high-temperature requirement serine protease A (HtrA)chaperone family [1]
The immunostaining analyses indicated that the neuronal OMI/HTRA2 staining was more pronounced in the frontal cortex of the Alzheimer’s disease (AD) compared to the control brain
Quantitative analysis revealed a significant increase of diffuse cytosolic staining of OMI/HTRA2 in the frontal cortex of the AD compared to control brains, indicating that the release of active OMI/ HTRA2 into the cytosol can be involved in initiation of cell death in the AD brain (Fig. 1c)
Summary
OMI/HTRA2 is a mitochondrial serine protease and member of the high-temperature requirement serine protease A (HtrA)chaperone family [1]. It is nuclear encoded and synthesized in the nucleus as a precursor protein containing a mitochondrial target sequence. OMI/HTRA2 is important for several cellular processes including mitochondrial function, autophagy [4], chaperone activity [5], and apoptosis [6] It promotes cell survival by the maintenance of mitochondrial homeostasis [7,8,9], while under stressful condition it may switch from a protector into pro-apoptotic factor [10,11,12,13]
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