Abstract
We recently demonstrated that chemical proteasome inhibition induced inner retinal degeneration, supporting the pivotal roles of the ubiquitin–proteasome system in retinal structural integrity maintenance. In this study, using beclin1-heterozygous (Becn1-Het) mice with autophagic dysfunction, we tested our hypothesis that autophagy could be a compensatory retinal protective mechanism for proteasomal impairment. Despite the reduced number of autophagosome, the ocular tissue morphology and intraocular pressure were normal. Surprisingly, Becn1-Het mice experienced the same extent of retinal degeneration as was observed in wild-type mice, following an intravitreal injection of a chemical proteasome inhibitor. Similarly, these mice equally responded to other chemical insults, including endoplasmic reticulum stress inducer, N-methyl-D-aspartate, and lipopolysaccharide. Interestingly, in cultured neuroblastoma cells, we found that the mammalian target of rapamycin-independent autophagy activators, lithium chloride and rilmenidine, rescued these cells against proteasome inhibition-induced death. These results suggest that Becn1-mediated autophagy is not an effective intrinsic protective mechanism for retinal damage induced by insults, including impaired proteasomal activity; furthermore, autophagic activation beyond normal levels is required to alleviate the cytotoxic effect of proteasomal inhibition. Further studies are underway to delineate the precise roles of different forms of autophagy, and investigate the effects of their activation in rescuing retinal neurons under various pathological conditions.
Highlights
The accumulation of toxic protein aggregates is a hallmark feature of many neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis [1]
We previously reported that the pharmacological inhibition of proteasome in the retina induced an accumulation of poly-ubiquitinated proteins, leading to cell loss in the ganglion cell layer (GCL) [29], which is resistant to an array of pharmacological agents, such as antioxidants and endoplasmic reticulum (ER) stress inhibitors
We demonstrated that only the mammalian target of rapamycin-independent autophagy activators could protect against proteasome impairment-induced cytotoxicity in human neuroblastoma cells
Summary
The accumulation of toxic protein aggregates is a hallmark feature of many neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis [1]. Proteasome inhibition in animal models, by genetic or pharmacological means, closely mimics the pathology and symptoms of neurodegenerative diseases, such as the aggregation of ubiquitinated proteins, formation of inclusion bodies, and neuronal cell death [6,7,8,9,10] Another major intracellular pathway regulating the clearance of aberrant protein is autophagy, which operates in a closely interlinked manner to the UPS [11]. The genetic deletion of autophagy-related genes in neuronal cells led to neurodegeneration [13,14], whereas activation of autophagy via chemical or genetic means, was shown to enhance the clearance of disease-associated protein aggregates [11] These two major protein degradation control systems, the UPS and autophagy, are effective cellular defense mechanisms in neurons and may be potential therapeutic targets for neurodegenerative diseases that are caused by neurotoxic protein accumulation and aggregation
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