Two well-known types of autophagy exist in eukaryotes: microautophagy and macroautophagy. While microautophagy involves the invagination of membranes in endosomes or lysosomes to incorporate and degrade cytosolic materials, macroautophagy is characterized by the formation of double-membraned structures called autophagosomes.
This article delves into the role of macroautophagy, often referred to as “autophagy,” in the context of neurodegenerative diseases, focusing on its implications for conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and glaucoma.
The Mechanisms of Autophagy
Macroautophagy, commonly referred to as autophagy, plays a pivotal role in cellular homeostasis. It is mediated by a unique organelle called the autophagosome, a double-membraned structure that engulfs cellular components destined for degradation. Several autophagy-related genes (Atg) have been identified in yeast, and their mammalian orthologues have been discovered. Beclin 1/Atg6, a key Atg protein, is central to macroautophagy as it regulates autophagosome formation within the Beclin 1 complex.
Macroautophagy in Neurodegenerative Diseases
Autophagy plays a significant role in maintaining cellular health, particularly in the context of neurodegenerative diseases.
Conditions such as Alzheimer’s disease (AD), Parkinson’s disease, ALS, and glaucoma are characterized by the accumulation of misfolded proteins, dysfunctional organelles, and damaged mitochondria. Impairment of autophagy in these conditions leads to the buildup of cellular waste, contributing to disease progression.
In response to stimuli like rapamycin treatment or starvation, autophagy is upregulated, leading to increased numbers of autophagic structures, including isolation membranes, phagophores, autophagosomes, and autolysosomes. The quantification of autophagic flux, as recommended by recent guidelines for autophagy research, provides a dynamic view of autophagy’s role in cellular health. LC3-II, the phosphatidylethanolamine-conjugated form of LC3, is a reliable marker for autophagosomes.
However, the interpretation of LC3-II levels should be performed cautiously, as the sensitivity to LC3-I and LC3-II may vary with different antibodies. Comparing changes in LC3-II with housekeeping proteins like β-actin is suggested for accurate measurements. Additionally, complementary assays like the p62/SQSTM1 protein assay are essential. Elevated p62 levels are associated with autophagy inhibition, making it a pivotal player in neurodegenerative diseases, such as AD and ALS.
The Role of Autophagy in Glaucoma
Glaucoma is a neurodegenerative disease characterized by various contributing factors, including elevated intraocular pressure (IOP), microvasculature impairment, tumor necrosis factor (TNF) levels, oxidative stress, aging, genetic aspects, axonal flow disruptions, collagen changes, glial activation, and mitochondrial dysfunction.
It is a leading cause of irreversible blindness worldwide, with optic nerve degeneration and visual field defects being hallmarks of disease progression. While reducing IOP remains the standard treatment for glaucoma, it does not always halt disease progression.
Glaucomatous histological changes involve the loss of retinal ganglion cell (RGC) axons and RGC death. Neuroprotection strategies have been explored extensively, including the use of memantine, an N-methyl-D-aspartate (NMDA) inhibitor. However, these approaches have not yielded significant positive results.
Conclusion
Autophagy, particularly macroautophagy, plays a crucial role in maintaining cellular health and has significant implications for neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, ALS, and glaucoma. In glaucoma, where optic nerve degeneration and RGC death are central to disease progression, a deeper understanding of the molecular aspects within axons and autophagy processes may offer new avenues for halting the disease’s advancement. While current research has uncovered much about autophagy’s role in these conditions, further investigations are essential for developing potential therapeutic interventions that target autophagic pathways and enhance neuroprotection in the face of neurodegenerative diseases.
reference link: https://www.sciencedirect.com/science/article/pii/S0098299723000572
