Related Experiment Video

Updated: May 15, 2025

A Protocol to Evaluate and Quantify Retinal Pigmented Epithelium Pathologies in Mouse Models of Age-Related Macular Degeneration
09:24

A Protocol to Evaluate and Quantify Retinal Pigmented Epithelium Pathologies in Mouse Models of Age-Related Macular Degeneration

Published on: March 10, 2023

1.4K

MLST8 overexpression in RPE cells disrupts autophagy through novel mechanisms affecting AMD pathogenesis

Sridhar Bammidi1, Sayan Ghosh1, Olivia Chowdhury2

  • 1Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Autophagy
|April 10, 2025
PubMed

Insights

Dysfunctional autophagy in the retinal pigment epithelium, driven by mechanistic target of rapamycin (MTOR) signaling, causes age-related macular degeneration (AMD). Inhibiting MTOR or enhancing CRYBA1 restores autophagy and RPE integrity, offering potential AMD therapies.

Area of Science:

  • Ophthalmology
  • Cell Biology
  • Genetics

Background:

  • Age-related macular degeneration (AMD) is a primary cause of vision loss in older adults.
  • Retinal pigment epithelium (RPE) dysfunction is a key factor in AMD pathogenesis.
  • Autophagy is a critical cellular process for maintaining RPE health.

Purpose of the Study:

  • To investigate the role of mechanistic target of rapamycin (MTOR) signaling in RPE dysfunction and AMD.
  • To explore the impact of MTOR upregulation on autophagy within the RPE.
  • To identify potential therapeutic targets for AMD by modulating autophagy.

Main Methods:

  • Development of a novel MLST8 knock-in mouse model with RPE-specific MTOR overexpression.
  • Assessment of autophagy markers, including autophagosome formation and LC3 processing.
  • Evaluation of RPE integrity and AMD-like pathology in the animal model.
  • Treatment with MTOR inhibitor torin1 and assessment of CRYBA1 overexpression effects.

Main Results:

  • Increased MTOR signaling in RPE suppressed autophagy by inhibiting autophagosome formation and LC3 processing.
  • This disruption led to autophagosome accumulation, defective autolysosome formation, and RPE dysfunction.
  • AMD-like pathologies, including subretinal debris and photoreceptor degeneration, were observed.
  • MTOR inhibition or CRYBA1 overexpression rescued autophagy defects and restored RPE integrity.

Conclusions:

  • MTOR complexes 1 and 2 (MTORC1/2) signaling disruption of autophagy drives AMD-like pathology in the RPE.
  • Autophagy regulation presents a promising therapeutic strategy for vision-threatening AMD.
  • This study highlights a novel mechanism linking MTOR, autophagy, and AMD pathogenesis.
Keywords:
Age-related macular degenerationMLST8MTORC1MTORC2autophagyretinal pigment epithelium

More Related Videos

Isolation of Primary Mouse Retinal Pigmented Epithelium Cells06:21

Isolation of Primary Mouse Retinal Pigmented Epithelium Cells

Published on: November 4, 2022

4.8K
Isolation, Culture, and Genetic Engineering of Mammalian Primary Pigment Epithelial Cells for Non-Viral Gene Therapy09:46

Isolation, Culture, and Genetic Engineering of Mammalian Primary Pigment Epithelial Cells for Non-Viral Gene Therapy

Published on: February 26, 2021

3.1K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.3K
Autophagy01:27

Autophagy

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
4.1K