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Panic! At the Cellular Level:

Autophagy and Neurological Abnormalities

By Chineze Egwudo

Scientists have recently begun to understand the relationship between a cellular mechanism called autophagy and healthy brain function. Autophagy, derived from the Greek word autophagos for self-devouring, is a normal process carried out by cells in which a cell digests part of its own contents. It is usually initiated by the cell’s instinct to prevent possible harm from worn-out or dysfunctional cellular components that no longer serve their prescribed function.4 Through autophagy, the cell can recycle those components and increase its ability to function more efficiently. When autophagy goes awry, however, it can cause major problems, especially for neurons, which are particularly sensitive to any impairments of autophagy, and autophagy problems are implicated in many neurodegenerative diseases.1

How do cells do it?

The process begins when a cell detects the cellular components that it wants to degrade. During the first phase, initiation, a double-membrane that will eventually surround the target macromolecule begins to form.3 In the elongation phase, the membrane grows rapidly, and it slowly surrounds the cellular component that will be digested, developing into a vesicle called an autophagosome. Once an autophagasome matures, it fuses its membrane with that of a cellular organelle called a lysosome, connecting their interiors.3 Enzymes within the lysosome initiate the breakdown of the cellular matter that was previously engulfed during the expansion phase.

The cell’s ability to break down its organelles and proteins down into their original macromolecules is advantageous in two major ways: First, cells can clean themselves up, getting rid of intracellular components that are useless or possibly harmful, Second, those components are effectively recycled, since they are broken down into macromolecules such as amino acids that are beneficial for cell growth. This can provide a survival mechanism; during times of starvation, the cell’s ability to produce macromolecules this way provides an important boost in energy levels.4

The problem arises when cells lose intuition. The inability to regulate autophagy can have drastic effects at the cellular level that eventually lead to disease. Too little autophagy leads to a buildup of toxic cellular matter such as mutant proteins and damaged organelles.1 In Parkinson’s disease, for example, it is believed that certain Parkinson’s-causing mutations reduce autophagy of damaged mitochondria, which may initiate neuron death.1 Although why this happens is not fully understood, scientists know an excessive amount of autophagosomes is characteristic of Parkinson’s and Alzheimer’s disease; this may indicate increased autophagy, perhaps in an attempt by the cell to deal with autophagy-related problems, or that autophagy is initiated but not completed quickly enough.4

On the other hand, excessive or unchecked autophagy leaves cells vulnerable to the loss of essential organelles, and their regular tasks are not carried out as efficiently. For example, it is known that autophagy in liver cells helps control blood sugar.5 It has been observed in mice that excessive liver autophagy would lead to an unwarranted spike in blood glucose levels as a result of the conversion of amino acids to glucose.5 Erratic behavior such as this can cause major problems and lead to cell death, which is ironically what autophagy aims to prevent.

Autophagy and Brain Disease

Neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s are strongly connected to abnormalities in autophagic processes.1 The reason for the connection likely lies in the unique nature of neurons. Neurons need to survive for an organism’s lifetime, so they have a longer period in which they are accumulating waste and in which that might pose a problem for the organism than most cells.1 They also stop undergoing cell division, so unlike most cells their waste is not diluted by being split between two new cells.1 This makes autophagy especially important for keeping them healthy.

Also, neurons are larger and longer than most other cells; unlike most cells, their cell bodies have a special extension called an axon that is long and thin and allows a signal to be sent from one neuron to another. Although autophagosomes occur all over the cell, including in parts of the axon far from the cell body, their contents are typically only fully digested when they are transported near to the cell body, as that is where most lysosomes are most active.6 Slight disruptions of lysosome activity can disrupt the transport of autophagosomes, so they build up in the axon.6 This blocking of transport can eventually cause axon death.7 Thus, neurons are heavily dependent on good lysosome function and autophagy for many reasons, and the nervous system is easily affected by unusual autophagic behavior.

The intricate autophagy-lysosome dynamic can be identified in brain disease. Alzheimer’s disease is recognized by the accumulation of misfolded amyloid-β proteins, which are formed from the breakdown of the amyloid precursor protein.8 Interestingly enough, the system of lysosomes that play a role in autophagy also play a significant role in making sure that the amyloid protein is created and functions properly. Mutations in this protein and proteins involved in the breakdown of amyloid-β are known causes of Alzheimer's disease.8 Similarly, Parkinson’s disease can be traced back to protein activity. In this case, mutations in ɑ-synuclein allow it to avoid periodic breakdown that is essential for the well being of the cell.9 This results in the accumulation of possibly dangerous proteins and soon after, autophagic processes scramble to take over the role of ɑ-synuclein degradation.9 The overworking of these processes leads to an abundance of autophagosomes eager to bind with lysosomes. The overall neuron death and less frequent activity of the neurotransmitter dopamine that arises are both defining characteristics of Parkinson's disease.9

While autophagy presents a way to understand neurological disorders, the extent to which mishaps in lysosomal function and in turn autophagic processes affect brain diseases such as Parkinson’s and Alzheimer’s is still unclear. This is mainly because of limited knowledge of the metabolic pathways involved in autophagy; the amount of waste and frequency at which the waste is degraded is often unclear. This contributes to the difficulty of creating effective treatments for these serious diseases. Despite this frustration, it is clear that one foundation of long-term neuronal health is healthy autophagic systems.2

References

  1. Nixon, Ralph A., and Dun-Sheng Yang. "Autophagy and Neuronal Cell Death in Neurological Disorders." Cold Spring Harbor Perspectives in Biology. October 2012. Accessed March 08, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475163/.
  2. "Autophagy in neuroprotection and neurodegeneration: a question of balance." Autophagy in neuroprotection and neurodegeneration: a question of balance, Future Neurology, Future Medicine. Accessed March 08, 2017. http://www.futuremedicine.com/doi/abs/10.2217/14796708.3.3.309.
  3. Yang, Xue. "The role of autophagy induced by tumor microenvironment in different cells and stages of cancer." The role of autophagy induced by tumor microenvironment in different cells and stages of cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384293/pdf/13578_2015_Article_5.pdf.
  4. Mizushima, Noboru. "Autophagy: process and function." Genes & Development. January 01, 1970. Accessed March 08, 2017. http://genesdev.cshlp.org/content/21/22/2861.long.
  5. Ezaki, Junji, Naomi Matsumoto, Mitsue Takeda-Ezaki, Masaaki Komatsu, Katsuyuki Takahashi, Yuka Hiraoka, Hikari Taka, Tsutomu Fujimura, Kenji Takehana, Mitsutaka Yoshida, Junichi Iwata, Isei Tanida, Norihiko Furuya, Dong-Mei Zheng, Norihiro Tada, Keiji Tanaka, Eiki Kominami, and Takashi Ueno. "Liver autophagy contributes to the maintenance of blood glucose and amino acid levels." Autophagy. July 2011. Accessed March 08, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149698/.
  6. Lee, Sooyeon, Yutaka Sato, and Ralph A. Nixon. "Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy." The Journal of Neuroscience. May 25, 2011. Accessed March 08, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351137/.
  7. Coleman, Michael. "Axon Degeneration Mechanisms: Commonality Amid Diversity". Nature Reviews Neuroscience. N.p., 2005. Web. 8 Mar. 2017.
  8. Funderburk, Sarah F., Bridget K. Marcellino, and Zhenyu Yue. "Cell “Self-Eating” (Autophagy) Mechanism in Alzheimer’s Disease." The Mount Sinai journal of medicine, New York. January 2010. Accessed March 08, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835623/.
  9. Lynch-Day, Melinda A., Kai Mao, Ke Wang, Mantong Zhao, and Daniel J. Klionsky. "The Role of Autophagy in Parkinson’s Disease." Cold Spring Harbor Perspectives in Medicine. April 2012. Accessed March 08, 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312403.

 

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