Purchase this article with an account.
Jussi J Paterno, Adrian Smedowski, Maria Hytti, Marialaura Amandio, Anna-Kaisa Ruotsalainen, Henri Olavi Leinonen, Heikki Tanila, Anna-Liisa Levonen, Pasi Tavi, Anu Kauppinen, Kai Kaarniranta; Nuclear factor-erythroid 2-related factor-2 (Nrf2) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) deficient mice: Dissecting the antioxidant regulation pathways affects retinal autophagy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6027.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Autophagic clearance participates in the regulation of proteostasis in the retina. Here, we describe a mouse model, deficient in two major transcriptional factors regulating antioxidant defense response, that mimic autophagy decline in retinal pigment epithelium (RPE).
Nrf2–/– PGC-1α–/– double knock-out (DKO) mice and age-matched wild-type controls on a C57BL/6J background were housed in groups on a 12-hour light/dark cycle and given food and water ad libitum. All procedures were in compliance with the ARVO statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Finnish National Animal Experiment Board. Optical coherence tomography (OCT) of retina and dark-adapted electroretinogram (ERG) were recorded in young adult (3.5 to 4.5 months old) and aged (12 to 13.5 months old) DKO mice and controls. Retinal tissue sections were immunostained with primary antibodies against 4-hydroxynonenal (4-HNE), ubiquitin, human antigen R (HuR, embryonic lethal abnormal vision (ELAV)-like protein 1), sequestosome 1 (SQSTM1, nucleoporin p62), beclin-1, and microtubule-associated proteins 1A/1B light chain 3B (LC3).
Aged Nrf2/PGC1α–/– mice developed RPE degeneration, associated with upregulation of oxidative stress (4-HNE), protein aggregation (ubiquitin), selective autophagy of aggregate-prone proteins (HuR, p62) and overall autophagy (beclin-1, LC3). These changes were accompanied by impaired visual function as assessed by ERG. Young adult DKO (n = 6) and control (n = 6) mice did not differ in their a- and b-wave amplitudes (p > 0.05), but among the aged mice both the a- and b-wave amplitudes were smaller in DKO (n = 7) compared to control mice (n = 7, a-wave: p < 0.05; b-wave: p < 0.01).
Our findings suggest that combined Nrf2 and PGC-1α deficiency increases oxidative stress and protein aggregation, and affects autophagy. This coincides with the retinal degeneration and decreased visual function observed in this promising animal model of age-related retinal degeneration.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
This PDF is available to Subscribers Only