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Enrique de la Rosa, Natalia Rodriguez-Muela, Hiroshi Koga, Lucia Garcia-Ledo, Pedro de la Villa, Ana Cuervo, Patricia Boya; Autophagy disregulation in the retina during aging and neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4576.
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Accumulation of undegraded proteinaceus material represents a hallmark in many retinopathies including age-related macular degeneration, the major cause of blindness in the elderly population. Autophagy contributes to maintain cellular homeostasis through the removal of damaged cellular components in lysosomes. Although alterations in autophagic function underlie a growing number of human diseases, very little is known about the contribution of this quality control mechanism to the retinal pathophysiology.
To determine how aging affects the functional state of autophagy in the different cell types of the retina, we compared young and old C57B6/J mice. In addition, we analyzed the consequences of macroautophagic blockage in retinal quality control by crossing the conditional Atg5 knockout animals (Atg5flox/flox) with the nestin-Cre mice to delete Atg5 in neural precursors. In both models, we determined several parameters related with autophagy, the levels of apoptosis, as well as the visual function by electroretinography.
We found that autophagic flux is less efficient in the aged retinas in both basal and under starvation conditions. In parallel, we found increased levels of lipofuscin, ubiquitinated proteins and p62 in all retinal layers from old C57B6/J mice. Decreased expression of the mRNA of the autophagy regulator Beclin1, a main component of the initiation complex, and of Atg7, the limiting enzyme for the elongation of the autophagosome membrane, were also observed in the aged mice. Further, we found TUNEL-positive nuclei in the retina from Atg5flox/flox; nestin-Cre mice, as well as a clear reduction in their visual function.
We have identified a primary malfunction of macroautophagy in the aging retina that may contribute to the age-related retinopathies and reduction of visual function.
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