Abstract Autophagy is a fundamental catabolic process that facilitates the degradation and recycling of cellular components like protein aggregates and defective organelles. However, the precise role of constitutive autophagy in regulating retinal ganglion cell (RGC) function and survival remains largely undefined. Here, we demonstrate that RGCs exhibit a robust and highly active constitutive autophagy. Furthermore, the selective autophagy knockout in RGCs induces neurodegeneration in Atg7 f/f and Atg5 f/f conditional knockout mice. Deficient autophagy, induced by AAV2-Cre in Atg7 f/f , Atg5 f/f mice, or by tamoxifen treatment in Atg7 f/- ; Nestin-CreERT2 + mice, resulted in significant and progressive functional and structural loss of RGCs and optic nerve degeneration. Immunostaining and transmission electron microscopic analysis revealed that deficient autophagy in RGCs led to the accumulation of damaged organelles, including swollen mitochondria, distended endoplasmic reticulum, synaptic vesicles, and enlarged Golgi apparatus within the RGC soma. These pathological changes were associated with increased p62, LC3B, and incomplete autophagosomes in the RGC soma. Notably, mass spectrometry analysis identified the accumulation of proteins associated with intracellular organelles, cellular architecture, the cytoplasm, and the ribonucleoprotein complex. Our findings indicate that deficient autophagy in RGCs results in the accumulation of defective organelles within the RGC soma, ultimately contributing to neurodegeneration.
Sundaresan et al. (Sat,) studied this question.