What is autophagy?
Autophagy is a critical process in living organisms and cells by which biomolecules and cellular organelles are degraded through a series of steps into small pieces for recycling or riddance. Most common among these biomolecules and cellular organelles are misfolded or unfolded proteins. Autophagy means “self-eating” in Greek. It was first brought up in 1963 by Christian de Duve (Klionsky et al. 2008), a Belgian cytologist and biochemist. Autophagy can be classified into three different categories: micro-autophagy, macro-autophagy, and chaperone-mediated autophagy (CMA). Autophagy plays a critical role in removing abnormal proteins and maintaining cellular equilibrium. The autophagy pathway is complex, involving multiple steps within a regulatory network. The classic macro-autophagy pathway starts by forming a specialized membrane structure called a phagophore. The growth of the phagophore is promoted by a VPS34 complex, leading to the generation of autophagosomes that capture the targets. In the end, autophagosomes merge with lysosomes, which are filled with various digestive enzymes, to break down the captured targets. The entire pathway is well monitored and regulated by a series of molecules termed autophagy-related proteins (ATGs) and others, including mTORC1, AMPK, TEFB, etc. (Zapata-Muñoz et al., 2021).
What are neurodegenerative diseases?
Neurodegenerative diseases are a group of disorders in the central and peripheral
nervous system in which neurons are damaged over time and eventually die. This group includes Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, as well as several other disorders. The majority of patients in this group are diagnosed at an advanced age, although some of the patients are diagnosed at a younger age. As there are currently no methods to reverse the degenerative process of neurons, no cures exist at this time. Treatments are available for each disorder to ameliorate the symptoms.
The pathogenesis of neurodegenerative diseases is often characterized by the deposition of misfolded proteins, such as tau, alpha-synuclein, and huntingtin, inside or outside neurons. These misfolded proteins cause chronic and progressive nerve cell death. This observation indicates the possible linkage of the autophagy process to the pathogenesis of these neurodegenerative diseases.
Relations between autophagy and Neurodegenerative disorders
Although the underlying mechanisms for these neurodegenerative disorders remain elusive and the causative roles of autophagy in disease origin and progress are still to be investigated, autophagy dysfunctions have been implicated in several neurodegenerative disorders.
For example, a large amount of evidence has come to show that anomalies in the autophagy pathway have contributed to pathogenesis (Menzies et al. 2017). Multiple gene mutations in Alzheimer’s disease have been found to be conducive to the dysfunction of autophagy networks. The gene PICALM mutation can disrupt autophagosome formation, cargo (a group of proteins identified and transported together) recognition, autophagic cargo, and autolysosome formation. Gene Tau mutation has been found to disrupt autophagic cargo and autolysosome formation. Similarly, the gene VPS 35 in Parkinson’s disease has also been shown to disrupt autophagosome formation and lysosomal function.
In addition, several studies have shown that gene mutations in the autophagy pathway can lead to neurological disorders. One is childhood ataxia, where the ATG5 E122D mutation was identified (Kim et al. 2016). The E122D mutation disrupts the formation of phagophores and autophagosomes. Another one is static encephalopathy of childhood with a gene mutation in WDR45, which encodes for the protein WIPI4. Protein WIPI4 is a critical autophagic lipid sensor that promotes autophagosome maturation. The mutation in gene WDR 45 causes static encephalopathy in childhood and neurodegeneration in adulthood. The phenotypes of this type of patient include poor motor coordination, learning and memory issues, etc.
Why it matters?
The role of autophagy in the pathogenesis of neurodegenerative diseases, whether causative or not, would allow the scientific community to find more treatment options and hopefully cure the diseases. There have not been any cures for neurodegenerative disorders; the vast majority of treatments are either replacement therapies such as Levodopa for Parkinson’s disease patients or symptom therapies such as Galantamine for Alzheimer’s disease patients.
Regarding autophagy, one approach to treatment is to induce autophagy using small molecules. This method would be particularly effective for those neurodegenerative disorders with aggregate-prone proteins such as mutant Huntington in Huntington’s disease (HD), alpha-synuclein in Parkinson’s disease (PD), and tau in Alzheimer’s disease (AD). By increasing the level of autophagy, it would allow over-produced misfolded or unfolded proteins to be degraded, cleared, and removed from neurons, thereby preventing neurons from degenerating, and eventually dying. For example, multiple small molecules have been found effective in inducing autophagy (Menzies et al. 2017). These small molecules can be divided into two groups: mTOR-dependent and mTOR-independent. Rapamycin and rapalogs acting in a mTOR-dependent way have shown efficacy as autophagy inducers in animal models of AD, PD, HD, and prion disease. mTOR-independent inducers such as Trehalose show significant benefits in mouse models of AD, PD, HD, etc. Metformin, Berberine, Methylene, and Nilotinib have also demonstrated similar efficacy in mouse models of multiple neurodegenerative disorders.
The mechanisms and features of known inducers on the autophagy pathway. Excerpts from Menzies et al., 2017. The complete form can be found here.
Conclusion
The efficacy and significance of autophagy inducers in regulating the autophagy pathway have presented new frontline treatment solutions and cures for those seeking relief from neurodegenerative disorders; however, some caveats need to be pointed out. For example, contrary to what is anticipated, the application of rapamycin to the mutant model of ALS has promoted neurodegeneration and decreased the life span of the mouse model (Zhang et al., 2011). Plus, the data from another study (Tanik et al., 2013) has also shown that the upregulation of autophagy might have impaired autophagosome maturation in alpha-synuclein aggregate-containing cells.
Dissecting the autophagy pathway is a multifaceted task, and there are still a great number of puzzles in this pathway that remain to be solved and pieced together. However, it will be safe to assume that with increased puzzles solved on this autophagic flux, autophagy-based therapeutics will hold the key to curing neurodegenerative disorders in the end.
Written By: Yuanxi Zhang, MD, MS
References:
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Tanik, S. A., Schultheiss, C. E., Volpicelli-Daley, L. A., Brunden, K. R., & Lee, V. M. (2013). Lewy Body-like α-Synuclein Aggregates Resist Degradation and Impair Macroautophagy. Journal of Biological Chemistry, 288(21), 15194-15210.
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