Intartaglia Daniela, Giamundo Giuliana, Naso Federica, Nusco Edoardo, Di Giulio Simona, Salierno Francesco Giuseppe, Polishchuk Elena, Conte Ivan
Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Department of Biology, University of Naples Federico II, Naples, Italy.
Front Aging Neurosci. 2022 Jun 30;14:878958. doi: 10.3389/fnagi.2022.878958. eCollection 2022.
Autophagy is a critical metabolic process that acts as a major self-digestion and recycling pathway contributing to maintain cellular homeostasis. An emerging field of research supports the therapeutic modulation of autophagy for treating human neurodegenerative disorders, in which toxic aggregates are accumulated in neurons. Our previous study identified Ezrin protein as an inhibitor of autophagy and lysosomal functions in the retina; thus, in turn, identifying it as a potential pharmacological target for increasing retinal cell clearance to treat inherited retinal dystrophies in which misfolded proteins have accumulated. This study aimed to verify the therapeutic inhibition of Ezrin to induce clearance of toxic aggregates in a mouse model for a dominant form of retinitis pigmentosa (i.e., RHO). We found that daily inhibition of Ezrin significantly decreased the accumulation of misfolded RHO aggregates. Remarkably, induction of autophagy, by a drug-mediated pulsatile inhibition of Ezrin, promoted the lysosomal clearance of disease-linked RHO aggregates. This was accompanied with a reduction of endoplasmic reticulum (ER)-stress, robust decrease of photoreceptors' cell death, amelioration in both retinal morphology and function culminating in a better preservation of vision. Our study opens new perspectives for a pulsatile pharmacological induction of autophagy as a mutation-independent therapy paving the way toward a more effective therapeutic strategy to treat these devastating retinal disorders due to an accumulation of intracellular toxic aggregates.
自噬是一种关键的代谢过程，作为主要的自我消化和循环途径，有助于维持细胞内稳态。一个新兴的研究领域支持通过调节自噬来治疗人类神经退行性疾病，在这些疾病中，有毒聚集体在神经元中积累。我们之前的研究确定埃兹蛋白（Ezrin）是视网膜中自噬和溶酶体功能的抑制剂；因此，反过来，将其确定为增加视网膜细胞清除率以治疗错误折叠蛋白积累的遗传性视网膜营养不良的潜在药理学靶点。本研究旨在验证在显性遗传性视网膜色素变性（即RHO）小鼠模型中，抑制埃兹蛋白是否具有治疗作用，以诱导清除有毒聚集体。我们发现，每天抑制埃兹蛋白可显著减少错误折叠的RHO聚集体的积累。值得注意的是，通过药物介导的脉冲式抑制埃兹蛋白来诱导自噬，可促进与疾病相关的RHO聚集体的溶酶体清除。这伴随着内质网应激的减轻、光感受器细胞死亡的显著减少、视网膜形态和功能的改善，最终更好地保留了视力。我们的研究为脉冲式药理学诱导自噬开辟了新的前景，这是一种不依赖于突变的治疗方法，为治疗由于细胞内有毒聚集体积累而导致的这些毁灭性视网膜疾病铺平了道路，迈向更有效的治疗策略。
