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Förslaget inkom 2008-05-30

The role of Omi/HtrA2 protease activity in mitochondria during apoptosis in Alzheimer’s disease (AD)

Loss of Omi seems to play an important role in the mitochondrial function. In this project we deemed it important to investigate the role of Omi on the mitochondrial function related to cell death.

Upon apoptotic stimuli Omi releases into the cytosol binds to inhibitory of apoptosis proteins inhibit their activity and directly degrade them.The first link between Omi and neurodegeneration has been established by the identification of Omi as a presenilin-1-interacting protein in yeast two-hybrid assays.Further the neuromuscular disorders of motor neuron degeneration 2 mutant mice was shown as a result of the protease-inactive mutation of Omi.The mnd2 mice-derived fibroblast increased the susceptibility of mitochondria to induce the permeability transition, resulting in it being vulnerable to stress. Mutations screening of the Omi/HtrA2 gene in German PD patients provide also a novel link between mitochondrial dysfunction and neurodegeneration in PD. Previous studies in various model systems have demonstrated that HAX-1 possesses anti-apoptotic properties, and may suppress cell death through an interaction with pro-apoptotic proteins. Moreover, recent studies using cells from SCN patients have provided evidence that HAX-1 is critical for maintaining the inner mitochondrial membrane potential and protecting myeloid cells from apoptosis. The present study will characterize the Omi protease activity and its role on the proapoptotic protein, HAX-1 in AD. It seems that only pro-apoptotic functions have been studied so far and other functions of Omi remains to be studied in AD.

The specific aims: To investigate the role of Omi protease activity on HAX-1 degradation before and after apoptotic stimuli. To study what mechanism or signalling pathway is involved in interaction between presenilin(s)-Omi in mitochondria and how this regulates Omi protease activity following its action on HAX-1 degradation. To study the topology of HAX-1 in mitochondria.

Importance: Today there is no cure to help people suffering from memory problems and AD. The available therapies treat symptoms rather than cause and the cause of the disease is still unknown. Omi has been shown to interact with extreme C-terminus of PS and such interaction could stimulate Omi protease activity. If the activity of Omi is regulated by PS in mitochondria, the loss of activity or excess activity may cause mitochondrial dysfunction that lead to neurodegentration. Moreover, regulation of Omi protease activity by studying the mechanism of signalling pathways involved in mitochondrial function may help to understand this manner.


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