Bammidi Sridhar, Ghosh Sayan, Chowdhury Olivia, Babu Vishnu Suresh, Dutta Puja, Hose Stacey, Sinha Debasish
Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Physiology, University of Calcutta, Kolkata, India.
Autophagy. 2025 Apr 14:1-3. doi: 10.1080/15548627.2025.2491097.
Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, with dysfunction of the retinal pigment epithelium (RPE) central to disease pathogenesis. Using our uniquely developed MLST8 (MTOR associated protein, LST8 homolog) knock-in animal model with RPE-specific overexpression, which drives MTOR (mechanistic target of rapamycin kinase) upregulation, we demonstrate that increased MTOR complexes 1 and 2 in the RPE disrupts macroautophagy/autophagy by suppressing autophagosome formation genes and impairing MAP1LC3/LC3 processing. This leads to autophagosome accumulation and defective autolysosome formation, driving RPE dysfunction and AMD-like pathology, including subretinal debris build up and photoreceptor degeneration. Notably, MTOR inhibition with torin1 treatment or CRYBA1 overexpression rescues these defects, restoring autophagy and RPE integrity. Our findings reveal that autophagy disruption mediated by both MTORC1 and MTORC2 drives AMD-like pathology in our mouse model, establishing autophagy regulation as a promising avenue for therapeutic intervention in this vision-threatening disease.
年龄相关性黄斑变性（AMD）是老年人失明的主要原因，视网膜色素上皮（RPE）功能障碍是疾病发病机制的核心。利用我们独特开发的具有RPE特异性过表达的MLST8（雷帕霉素靶蛋白相关蛋白，LST8同源物）敲入动物模型，该模型驱动MTOR（雷帕霉素激酶的机制性靶标）上调，我们证明RPE中MTOR复合物1和2的增加通过抑制自噬体形成基因和损害MAP1LC3/LC3加工来破坏巨自噬/自噬。这导致自噬体积累和自噬溶酶体形成缺陷，驱动RPE功能障碍和AMD样病理变化，包括视网膜下碎片堆积和光感受器退化。值得注意的是，用托瑞米芬治疗或CRYBA1过表达抑制MTOR可挽救这些缺陷，恢复自噬和RPE完整性。我们的研究结果表明，在我们的小鼠模型中，由MTORC1和MTORC2介导的自噬破坏驱动了AMD样病理变化，确立了自噬调节作为这种威胁视力疾病治疗干预的一个有前景的途径。
