COINVOLGIMENTO DELLA PROTEINA CLIC1 NELL¿INSORGENZA E NEL PROCESSO NEURODEGENERATIVO DEL GLAUCOMA

CLIC1 is a member of an intracellular chloride channel family, CLIC, highly conserved in vertebrates. It has both soluble and membrane-integrated forms. Different studies demonstrate that several stimuli, like oxidation or pH changes, promote CLIC1 insertion in the membrane and a consequent generation of a chloride current. It has been reported that CLIC1 has an important role in different cell functions, such as migration, swelling or division of the cell, endocytosis and exocytosis, intracellular vesicles fusion, and apoptosis. CLIC1 and other CLIC family members are involved in cellular function not directly correlated with the ion channel activity in the plasma membrane. Recent studies have shown that CLIC1 may be involved in mediating neurotoxicity in Alzheimer’s disease. A previous work has shown that CLIC1 is upregulated and translocated in plasma-membrane in microglial cell (BV2) after treatment with amyloid beta peptide (Aβ) and in a triple mutant AD mouse brain. Inhibition of CLIC1 activity with the specific blocker (IAA 94) or expression by siRNA reduced reactive oxygen species (ROS), nitric oxide (NO) and TNFalpha production in microglial cells, leading to a neuroprotective effect in microglia-neuron co-cultures. The hypothesis is that CLIC1-dependent chloride current is required for Aβ-mediated ROS production by microglial cells, maintainig NADPH oxidase activity and providing the charge compensation to avoid membrane depolarization. Enhanced levels of Aβ in fibrillar or soluble forms, have been shown to cause neurotoxicity in neurodegenerative disorders. The accumulation of Aβ, has recently been critically involved, as well as widely descripted in Alzheimer’s disease, in the pathogenesis of ocular disease as age-related macular degeneration (ARMD) and glaucoma. Aβ is associated with impaired mitochondrial function, activation of cellular oxidases and generation of reactive oxygen species (ROS), leading to oxidative injury and alterations in neuronal ionic homeostasis. To date the molecular and cellular mechanisms involved in Aβ-mediated retinal neurotoxicity are still not well understood. Among all the other factors that participate to the glaucoma pathogenesis, oxidative damage caused by the production of reactive oxygen species (ROS) is certainly one of the prominent causes of retinal ganglion cell (RGC) death and optic nerve degeneration. Previous studies have shown that glaucoma has all the characteristics of a neurodegenerative disease: microglial activation, state of chronic inflammation, increase of extracellular Aβ, oxidative stress and neuronal death. In the last past years similarities have been discovered between glaucoma and Alzheimer’s disease. Starting from the data of CLIC1 involvement in mediating inflammatory response under Aβ over-expression condition in microglial cells and in AD brain, our aim was to characterize this protein in the retina, which is part of the CNS and that is more easily accessible. Hence the importance of our work is not just limited to understanding the…