Autophagy: Potential target for treating neurodegenerative disorders
Autophagy is a dynamic cellular pathway involved in the turn over of proteins, protein complexes, and organelles through lysosomal degradation. Defects in autophagy affect the intercellular communication and subsequently contributing to neurodegeneration. The presence of abnormal autophagy activity is frequently observed in selective neuronal populations in neurodegeneration seen in diseases like ALS, Alzheimer's, Parkinson's, and Huntington's disease.
Macroautophagy-referred to as autophagy literally means self-eating in Greek and is responsible for removal of long-lived protein and damaged organelles. Cellular physiology and energy metabolism are maintained by the constant supply of energy furnished by the power house of the cell called mitochondria. Cellular homeostasis depends on the timely clearance of damaged cellular organelles and proteins via pathways including autophagy. Homeostasis is Greek for same and steady. It refers to any process living things use to maintain stable conditions necessary for survival. Mitochondrial autophagy plays a role in cellular health. Neuronal cells are more sensitive to depletion of energy since most of their function depends on available energy. In the past few decades research has found that neurodegenerative disorder is associated with mitochondrial dysfunction. This leads to an accumulation of protein aggregates that ultimately end in neurodegeneration (Kumer et al. 2018). Motoneurons are the most polarized mammalian cells. Due to this, they are very dependent on efficient energy supply, proper clearance of damaged organelles, and abnormal protein accumulation. ALS is one of the most common motorneuron diseases. Among the almost 40 genetic factors that can cause ALS and related diseases. Autophagy is a central recycling process in the cell. Development of genetic manipulation in a cell-type and time specific manner has proven to be a fundamental step in locating where the autophagy breaks down. Organizations such as Michael J. Fox Foundation for Parkinson’s Research and Muscular Dystrophy Association have both provided funding for this research is an effort to halt the diseases affect by autophagy in their tracks (Valenzuela, Nassif, & Hetz, 2018).
What are they?
Neurons are particularly dependent on robust quality control of pathways to maintain cellular homeostasis and functionality throughout their extended lifetime. Autophagy has important functions in development of functions in development of the nervous system as well as in neuronal function and survival. Emerging evidence suggests novel pathways for intercellular co-ordination of quality control pathways between neurons to maintain homeostasis in the brain. Accumulation of misfolded proteins is a defining hallmark for the progression of various neurodegenerative diseases such as ALS, Huntington’s, Parkinson’s, or Alzheimer’s diseases. Autophagy performs diverse and compartment-specific functions in neurons. These functions may depend on age and type of neuron. So the function of autophagy in neurons may evolve to meet the demands of a developing and maturing nervous system. Glia cells make up 90% of the brain and are key regulators of neuronal homeostasis and function. Alterations in neuron-glia communication are a significant contributing factor to the progression of neurodegeneration. With this in mind it is hoped further research will find a way to capitalize on that point and develop a treatment or treatments to stop and treat these devastating neurodegenerative diseases like ALS and Alzheimer’s (Kulkavni, Chen, & Maday, 2018).
Cells rely on surveillance systems such as autophagy to handle protein alterations and organelle damage. Dysfunctional autophagy frequently leads to neurodegeneration. Genetic studies have found some proteins related to neurodegeneration such as Huntington participates in autophagy as one of their physiological functions. The involvement of defective autophagy in the progression of neurodegenerative diseases like Alzheimer’s, ALS, or Parkinson’s is now well established. Evidence supports many mechanisms autophagy failure in neurodegenerative disorders. Clinical translation of this wealth of knowledge is still at an early stage. And even though there have been limited success with pharmacological treatments of autophagy it is hoped future research will help alleviate this disorder (Scrivo et al. 2018).
The most prevalent pathological features of many neurodegenerative diseases are aggregation (collection of units or parts into a mass or whole) of misfolded proteins and loss of certain neuronal populations. Autophagy has the function of degrading aggregated proteins and damaged organelles. It has also been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders including Alzheimer’s, Parkinson’s, Huntington’s disease and ALS (amyotrophic lateral sclerosis). Pathological abnormalities of various neurodegenerative diseases are often associated with corresponding protein aggregations that result in a different cellular environment and sub-cellular compartments (Guo et al. 2018).
And what needs to be done.
There is a common pathology that is shared by several neurodegenerative disorders like Alzheimer’s, Parkinson’s, ALS that have been identified as an accumulation of misfolded proteins. Autophagy is a cellular function that takes care of abnormal proteins-including misfolded-it has been found that the onset and progression of these illnesses can be attributed to the autophagy activity (or lack of) in the neurons. In this research showed the potential uses for conventional Autophagy for treatment for several neurodegenerative diseases. It is hoped induction of Autophagy can potentially mitigate disease severity or possibly one day even stop one of the neurodegenerative diseases that take the lives of people every year (Fujikake, Shin, & Shimizu, 2018).
Autophagy is from Greek meaning either self-eating or eating of self and was first coined by Christian de Duve over 40 years ago. Autophagy is active at the basal level in most cell types where they play a housekeeping role in maintaining the integrity of organelles and proteins. There is growing evidence that mutation or lack of function of key autophagy genes can lead to neurodegenerative illnesses. This has caused autophagy to be seen as a new and potent modulator of disease progression that is both scientifically intriguing and clinically relevant (Glick et al, 2018).
In recent years there have been great strides in understanding what cell dysfunctions and death that leads to diseases like Parkinson’s Alzheimer’s Huntington’s and ALS. Mitochondria are commonly regarded as the powerhouse of the cell. They are involved in a multitude of cellular activities. Autophagy is part of the process to maintain cellular health. It helps keep the powerhouse in the cells-the mitochondria-working in an optimal fashion. The mitochondria are being studied in an effort to find an agent to help stop or prevent the diseases affected by dysfunctional autophagy. As the quality control of mitochondria and autophagy is closer studied it is a very hopeful treatment for these life-changing diseases can be found and soon (Franco-Iborra et al, 2018).
Franco-Iborra, S.,Vila, M., & Perier, C. (2018). Mitochondrial quality control in neurodegenerative disease: Focus on Parkinson’s disease and Huntington’s disease. Frontiers in Neuroscience, 12(342).
Fujikake,N., Shin, M. & Shimizu, S. (2018). Association between Autophagy and neurodegenerative diseases. Frontiers in Neuroscience.
Glick, D., Barth, S. & Macleod, K.F. (2018). Autophagy cellular and molecular mechanisms. Journal of Pathology, 221 (1).
Guo, F. et al. (2018). Autophagy in neurodegenerative diseases: Pathogenesis and therapy. Brain Pathology, 28(1).
Kulkavni, A., Chen, J., and Maday, S. (2018). Neuronal autophagy and intercellular regulation of homeostasis in the brain. Current Opinions in Neurobiology, vol. 51.
Kumer, A. et al. (2018). Autophagy and mitochondria targets in neurodegenerative disorders. CNS & Neurological Disorders-Drug Targets, 17(9).
Scrivo, A. et al. (2018). Selective autophagy as potential therapeutic target for neurodegenerative disorders. The Lancet Neurology, 17(9).
Valenzuela, V., Nassif, M. & Hetz, C. (2018). Unraveling the role of motoneuron Autophagy in ALS. Autophagy, 14(4).