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Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.
Parkin is a 465-amino acid residue E3 ubiquitin ligase, a protein that in humans and mice is encoded by the PARK2 gene. Parkin plays a critical role in ubiquitination – the process whereby molecules are covalently labelled with ubiquitin (Ub) and directed towards degradation in proteasomes or lysosomes. Ubiquitination involves the sequential action of three enzymes. First, an E1 ubiquitin-activating enzyme binds to inactive Ub in eukaryotic cells via a thioester bond and mobilises it in an ATP-dependent process. Ub is then transferred to an E2 ubiquitin-conjugating enzyme before being conjugated to the target protein via an E3 ubiquitin ligase. There exists a multitude of E3 ligases, which differ in structure and substrate specificity to allow selective targeting of proteins to intracellular degradation.
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.
PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.
Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.
Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford and Porter used electron microscopy to observe mitochondrial fragments in liver lysosomes by 1962, and a 1977 report suggested that "mitochondria develop functional alterations which would activate autophagy." The term "mitophagy" was in use by 1998.
Beth Cindy Levine was an American microbiologist. She was an investigator at the Howard Hughes Medical Institute (HHMI), Professor of Internal Medicine and Microbiology, Director of the Center for Autophagy Research and Charles Cameron Sprague Distinguished Chair in Biomedical Sciences at the University of Texas Southwestern Medical Center. She specialized in the field of autophagy; more specifically in its regulation and its role in diverse diseases, including cancer and infectious diseases. Levine was described as a pioneer in the field of modern mammalian autophagy.
Nix is a pro-apoptotic gene that is regulated by Histotoxic hypoxia. It expresses a signaling protein related to the BH3-only family. This protein induces autophagy, an intracellular function by which cytoplasmic components are delivered to the lysosome to be broken down and used elsewhere or excreted from the cell. This protein is important in development because it allows cells to have a consistent store of cellular components. It also holds an important role in the differentiation and maturation of erythrocytes and lymphocytes by the process of mitophagy with the help of its regulator BNIP3. Using a gene knockout technique in mice, scientists have been able to attribute this pruning of mitochondria and induction of cellular necrosis to the expression of the Nix gene. The Nix protein may be associated with certain kinds of cancer formation. In mouse models, loss of Nix resulted in a delayed onset of tumors for pancreatic cancer, and was additionally associated with reduced mitophagy and increased oxidative metabolism. Nix therefore may be a tumor promoter for pancreatic cancer.
Nektarios N. Tavernarakis is a Greek bioscientist, who studies Ageing, Cell death, and Neurodegeneration. He is currently Distinguished Professor of Molecular Systems Biology at the Medical School of the University of Crete, and the Chairman of the Board of Directors at the Foundation for Research and Technology, in Heraklion, Crete, Greece. He is also the founder and first Director of the Graduate Program in Bioinformatics of the University of Crete Medical School, and has served as Director of the Institute of Molecular Biology and Biotechnology, where he is heading the Neurogenetics and Ageing laboratory. He was elected Vice President of the European Research Council (ERC) in 2020, and Chairman of the European Institute of Innovation and Technology (EIT) Governing Board and Executive Committee in 2022.
The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.
Mitochondria-associated membranes (MAMs) represent regions of the endoplasmic reticulum (ER) which are reversibly tethered to mitochondria. These membranes are involved in import of certain lipids from the ER to mitochondria and in regulation of calcium homeostasis, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis.
Bradlee L. Heckmann is an American biologist, pharmacologist. Heckmann holds academic appointments as a neuroimmunologist at the Byrd Alzheimer's Center and USF Health Neuroscience Institute and is assistant professor in molecular medicine at the USF Health Morsani College of Medicine. Heckmann's research has been focused on understanding the regulation of inflammatory and metabolic processes in the central nervous system, with particular emphasis on neurodegenerative diseases including Alzheimer's disease and the role of the autophagy machinery in this setting.
Animal models of Parkinson's disease are essential in the research field and widely used to study Parkinson's disease. Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of the dopamine neurons in the brain, results in motor dysfunction, ultimately causing the four cardinal symptoms of PD: tremor, rigidity, postural instability, and bradykinesia. It is the second most prevalent neurodegenerative disease, following Alzheimer's disease. It is estimated that nearly one million people could be living with PD in the United States.
Erika L F. Holzbaur is an American biologist who is the William Maul Measey Professor of Physiology at University of Pennsylvania Perelman School of Medicine. Her research considers the dynamics of organelle motility along cytoskeleton of cells. She is particularly interested in the molecular mechanisms that underpin neurodegenerative diseases.
David A. Hood is a Canadian professor, exercise physiologist, and Director of the Muscle Health Research Centre at York University. A holder of an NSERC Tier I Canada Research Chair in Cell Physiology, Hood is credited with making significant research advances in understanding of the biology of exercise, mitochondria and muscle health.
Roberta Anne Gottlieb is an American oncologist, academic, and researcher. She is a Professor, and Vice-Chair of Translational Medicine in the Department of Biomedical Sciences at Cedars-Sinai Medical Center, and a Professor of Medicine at the University of California, Los Angeles.
AMBRA1 is a protein that is able to regulate cancer cells through autophagy. AMBRA1 is described as a mechanism cells use to divide and there is new evidence demonstrating the role and impact of AMBRA1 as a candidate for the treatment of several disorders and diseases, including anticancer therapy. It is known to suppress tumors and plays a role in mitophagy and apoptosis. AMBRA1 can be found in the cytoskeleton and mitochondria and during the process of autophagy, it is localized at the endoplasmic reticulum. In normal conditions, AMBRA1 is dormant and will bind to BCL2 in the outer membrane. This relocation enables autophagosome nucleation. AMBRA1 protein is involved in several cellular processes and is involved in the regulation of the immune system and nervous system.
Richard James Youle is an American neurobiologist and molecular biologist. He is a Distinguished Investigator and head of the Biochemistry Section at the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) in Bethesda, Maryland.
Zhenyu Yue is a Chinese academic researcher in the field of neurology and neuroscience, who is the Alex and Shirley Aidekman Professor at the Icahn School of Medicine at Mount Sinai, New York. He is known for his discovery of genes controlling autophagy, autophagy functions in central nervous system, molecular mechanism of neurodegenerative diseases, and modelling neurological diseases using genetic mouse models.
References
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- ↑ Evans, Chantell Skye (2015). "The biophysics of synaptotagmin-1 action".
- ↑ "People | Holzbaur Lab | Perelman School of Medicine at the University of Pennsylvania". www.med.upenn.edu. Retrieved 2022-10-20.
- ↑ "HHMI Hanna Gray Fellow / 2017—Present". 2017.
- ↑ "Chantell Evans, PhD: Examining the Links Between Damaged Mitochondria and Brain Diseases". Duke University School of Medicine. 8 December 2021. Retrieved 2022-10-20.
- ↑ "Chantell Evans | Duke Department of Cell Biology". www.cellbio.duke.edu. Retrieved 2022-10-20.
- 1 2 3 "The Brilliant 10: The top up-and-coming minds in science". Popular Science. 2022-10-19. Retrieved 2022-10-20.
- ↑ Evans, Chantell S; Holzbaur, Erika LF (2020-01-14). Harper, Wade; Pfeffer, Suzanne R (eds.). "Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons". eLife. 9: e50260. doi: 10.7554/eLife.50260 . ISSN 2050-084X. PMC 6959996 . PMID 31934852. S2CID 210193102.
- ↑ "CZI Science Diversity Leadership Award Grantees". Chan Zuckerberg Initiative. Retrieved 2022-10-20.
- ↑ "Scholars@Duke grant: How does selective autophagy dysfunction contribute to neurodegeneration?". scholars.duke.edu. Retrieved 2024-02-07.
- ↑ "Scholars@Duke grant: Training Program in Developmental and Stem Cell Biology". scholars.duke.edu. Retrieved 2024-02-07.
- ↑ "Scholars@Duke grant: Cell and Molecular Biology Training Program". scholars.duke.edu. Retrieved 2024-02-07.
- ↑ "Scholars@Duke grant: Investigating mitochondrial turnover in homeostasis and disease". scholars.duke.edu. Retrieved 2024-02-07.
- ↑ "Scholars@Duke grant: HHMI Hanna H. Gray Fellows Program: Mitochondrial surveillance in neuronal homeostasis and disease". scholars.duke.edu. Retrieved 2024-02-07.
- ↑ "Scholars@Duke grant: Neurobiology Training Program". scholars.duke.edu. Retrieved 2024-02-07.
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