Cellular homeostasis in the nervous system. Neuronal survival and autophagy imbalance during aging: implications for neurodegenerative diseases

We are focused on the retina as a suitable model to study normal and precocious aging, as well as neurodegeneration. It provides a window into the brain adequate for non- or little-invasive manipulations, as well as for direct imaging of the tissue. Indeed, protein aggregates reminiscent of those found in the brain of AD models and patients, are also found in the retina of AD models (Fig), as well as in some types of age-related retinal dystrophies.

We are studying in parallel normal aging in wild type animals, as well as precocious aging in several models including SAMP8 mouse (a model of sporadic AD; in collaboration with the group of Coral Sanfeliú), Atg5^flox/flox;Nestin-Cre mouse (a autophagy-deficient model) and rd10 mouse (a model of retinitis pigmentosa). In all cases, the aging process is reflected in retinal functional decay that can be monitored by electroretinography. We are characterizing the cellular processes underlying vision loss. Besides a process of pathological cell death, prominent in the acute degeneration occurring in rd10 mice, we are also studying synapse loss that could be involved in the chronic decay found in other models.

We are also testing the neuroprotective potential of proinsulin, a pro-survival growth factor during retinal development. Vision loss has been attenuated in all tested models, including normal aging, rd10 mice and SAMP8 mice.

In addition, we are also interested in investigating age-dependent retinal function monitored by electroretinography in autophagy deficient mice and in the mice models provided by other groups in the project in which accelerated aging is expected. In this regard and together with the group of Mª Dolores Ledesma, we are analyzing the role of autophagy in the neurodegenerative phase in Niemann Pick disease type A. Moreover, we are interested in pharmacological modulation of autophagy in the mouse models and effects on retinal function, cell death or protein/lipid accumulation.

Enrique and Patricia laboratory web: http://www.cib.csic.es/es/grupo.php?idgrupo=20