CHLORIDE INTRACELLULAR ION CHANNEL 1 AS A CUTTING EDGE BETWEEN NEUROGENESIS AND NEURODEGENERATION.

Chloride intracellular ion channel 1 (CLIC1) has peculiar properties compared to most known ion channels, in that it exists both as a soluble protein and as a membrane-integrated protein. Previous studies have shown that CLIC1 insertion into the plasma membrane is driven by different stimuli such as oxidation, cytoplasmic acidification, increased calcium concentration. Once inserted into the plasma membrane CLIC1 forms a chloride selective ion channel. The best characterized mechanism leading CLIC1 into the plasma membrane is cell oxidation. Our laboratory has previously shown that in microglia cells stimulation by amyloid beta peptides, one of the most common hallmarks of Alzheimer disease (AD), determines the increase of CLIC1-mediated current. Many studies have demonstrated that many AD patients show at first visual impairment rather than other cognitive deficits. AD patients show severe abnormalities in the structure and function of the retina, including retinal ganglion cells (RGCs) loss. Several cellular mechanisms precede RGCs degeneration, including oxidative stress. Therefore, in view of the oxidation-driven behavior of CLIC1, during my PhD, I analyzed CLIC1 expression in mouse retina. We found out that CLIC1 expression is increased in retinas of two different AD mouse models. Interestingly, CLIC1 increased expression is prior to the manifestation of the first cognitive symptoms, thus proposing CLIC1 as an early marker of neurodegeneration in AD. Although CLIC1 expression is largely increased in AD mouse retinas, CLIC1 is also expressed in wild type retinas, mainly in the gangliar layer, where the nuclei of RGCs, whose axons make up the optic nerve, are located. Thus, we wondered about the role of CLIC1 in the normal RGCs physiology. Our studies unraveled the crucial role of CLIC1-mediated current in axon outgrowth of RGCs, showing that the inhibition of the chloride current causes a reduced axon outgrowth that is parallel to an altered morphology of the growth cones and a reduced co-localization of CLIC1 with the actin cytoskeleton. Our results also suggest that CLIC1 involvement in axon outgrowth might be due to CLIC1 modulation by cAMP. Taken together our data propose cAMP, or cAMP homologues, as a putative tool to modulate CLIC1 transient expression at the plasma membrane and consequently axon outgrowth.