Omi is a mammalian heat-shock protein that selectively binds and detoxifies oligomeric amyloid-

The cellular generation of toxic metabolites and subsequent detoxification failure can cause the uncontrolled accumulation of these metabolites in cells, leading to cellular dysfunction. Amyloid- protein (A), a normal metabolite of neurons, tends to form toxic oligomeric structures that cause neurodegeneration. It is unclear how healthy neurons control the levels of intracellular oligomeric A in order to avoid neurodegeneration. Using immunochemical and biochemical studies, we show that the A-binding serine protease Omi is a stress-relieving heat-shock protein that protects neurons against neurotoxic oligomeric A. Through its PDZ domain, Omi binds preferentially to neurotoxic oligomeric forms of A rather than non-toxic monomeric forms to detoxify oligomeric A by disaggregation. This specific interaction leads not only to mutual detoxification of the pro-apoptotic activity of Omi and A-induced neurotoxicity, but also to a reduction of neurotoxic-A accumulation. The neuroprotective role of Omi is further supported by its upregulation during normal neurogenesis and neuronal maturation in mice, which could be in response to the increase in the generation of oligomeric A during these processes. These findings provide novel and important insights into the detoxification pathway of intraneuronal oligomeric A in mammals and the protective roles of Omi in neurodegeneration, suggesting a novel therapeutic target in neurodegenerative diseases.