FOXO Transcription Factors and Neurodegenerative Diseases

Introduction

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are tragic conditions that cause the loss of memory and motor control. As these diseases progress, patients eventually forget everything, including the faces of their loved ones and even their own identities, ultimately leading to a loss of autonomy and sense of self. Treatments that could cure these conditions or even halt their progression do not currently exist; however, recent breakthroughs in the fields of molecular biology and neuroscience have presented a new map to follow in the search for a treatment. In the last decade, scientists have begun investigating a special family of transcription factorsproteins that control which genes are expressed in a cellknown as forkhead box O class (FOXO) transcription factors. These FOXO transcription factors are a diverse and dynamic family of proteins that regulate essential functions of cells throughout our bodies. Scientists are pursuing research on FOXOs for their implications in neuron growth, health and death, and their potential influence on memory and motor control. FOXO transcription factors present an exciting new frontier in the search for a treatment that could contribute to ending the pain of neurodegenerative disease.

Background

In 2017, roughly 50 million individuals suffered from Alzheimer’s disease (AD), a condition that causes people to slowly lose their memories and identities due to nerve degeneration in the central and peripheral nervous systems.[1] This number is expected to increase by 9.9 million cases each year, causing more deaths in the United States than prostate cancer and breast cancer combined.[1] After AD, Parkinson’s disease (PD)—which is characterized by a loss of motor control—is the second most common neurodegenerative disease, with 40% of patients eventually developing dementia.[2]

Both of these neurodegenerative diseases involve the breakdown of neuronal axons in the central and peripheral nervous systems.[1, 2] This results in a decrease in connections between neurons, causing memory loss, impaired motor control, and cognitive decline in patients. The brain is like a computer, where the cords are axons and the connections are synapses. Any fraying or breaking of the cords would cause the computer to lose some of its connections, similar to what is seen in AD- and PD-afflicted brains. This phenomenon, known as axon degeneration, is the key symptom responsible for the neurological consequences of these neurodegenerative diseases.

A current model for neurodegenerative disease postulates that this axon degeneration, or “fraying,” occurs primarily in response to proteotoxic stress, a condition generated by the misfolding and aggregation of proteins that impairs the function of and puts enormous strain on the cell.[3, 4, 5] Like a jammed printer, when cells produce misshapen proteins, they essentially “break.” This “breaking” occurs when misfolded proteins interfere with cellular components such as the cell membrane, organelles, or proteins crucial to cell survival. Under healthy conditions, cells “unjam” themselves through a process called autophagy, in which a cell degrades or recycles the malfunctioning protein.[4] However, in neurodegenerative diseases such as AD and PD, this autophagy or “unjamming” mechanism fails, and all the misfolded proteins build up until the cell is under so much stress that it “breaks” and dies.[4]

Based on recent scientific evidence, it is theorized that FOXO transcription factors activate the autophagy or “unjamming” mechanism of the cell. As stated before, transcription factors are proteins that control which genes are expressed in the cell. FOXOs, for example, can activate genes that produce DNA repair proteins, proteins that keep cells from multiplying, proteins that can initiate cell death, and most important for AD and PD research, autophagy proteins.[6] Current research is investigating the idea that by activating the dormant FOXO transcription factors responsible for autophagy gene transcription in the neurons of AD- and PD-afflicted brains, the damage done to neurons by proteotoxic stress can be halted and possibly reversed.

This research, however, is slow-going due to the complicated nature of FOXO regulation. Because FOXO transcription factors have the ability to simultaneously activate genes for autophagy and genes for cell death, it is important for scientists to understand how these functions are regulated. A healthy cell will use many different signal pathways to regulate which genes FOXOs promote at any given time. Similar to how a person uses their eyes, ears and nose to determine which direction to walk, cells use all their “senses” to make decisions about which gene FOXOs need to activate. Furthermore, there are many different forms of FOXOs. Any FOXO-focused treatment of AD or PD would have to not only differentiate between FOXO functions but also sort through different FOXO isoforms as well. As exciting as the implications for FOXO research in neurodegenerative disease treatment are, it is important to realize that the process of scientific discovery is a long one due to the convoluted nature of molecular biology.

FOXO Research in Neurodegenerative Pathologies

Scientist now theorize that FOXO activation could be critical to the treatment of AD and PD based on evidence that suggests a critical role for FOXOs in the regulation of a neuron’s response to proteotoxic stress.[4, 6] This theory was given credibility by a study that knocked out FOXO genes in mice and analyzed the effect this had on the neural function and health of the mice.[4] To knock out a gene means to remove or disable that gene in an organism’s DNA sequence. By doing this, scientists can determine the function of the gene by examining what goes wrong in that organism’s physiology in the absence of the targeted gene’s function. The study found that FOXO knockout mice lost the ability to activate autophagy and developed motor and memory deficiencies characteristic of PD- and AD-linked axon degeneration.[4] Although these results only imply a correlation between FOXO activation and autophagy, scientists are able to use this theory to direct future investigations into how axon degeneration becomes out of control in neurodegenerative diseases.

In AD specifically, researchers have found that FOXOs are not expressed due to the excessive production of growth factors in damaged neurons.[3] Growth factors are messenger chemicals that tell cells to multiply or grow. It has been known for many years that growth factors inhibit FOXOs from being activated and that growth factor inhibition is protective in AD. However, only recently have scientists theorized that growth factors play a detrimental role in neurodegenerative disease because of their inhibition of FOXO activity.[6, 3, 7] The strong correlation between growth factor inhibition, FOXO activity, and AD symptom alleviation supports the idea that FOXOs combat AD by promoting autophagy in affected cells and relieving the proteotoxic stress that kills nerves.[7, 3, 4]

FOXO studies concerning PD report similar findings. The correlation between FOXO activation and the promotion of autophagy in PD mice are indicative of a crucial role of FOXOs in neurodegenerative disease. Researchers found that FOXO activation significantly reduced the progression of axon degeneration of PD mice, improving motor control, memory, and nerve health.[3] Most importantly, activation of FOXOs in PD mice resulted in the degradation of the misfolded proteins that cause axon fraying and neuron death.[3] To further explore FOXO-targeted treatments for PD and AD symptoms, it will be important in coming years to ascertain the exact mechanisms by which FOXOs promote autophagy as well as the mechanisms by which they are inhibited or “turned off” in neurodegenerative diseases.[3, 4, 5]  

Conclusion

FOXOs are diverse and dynamic proteins that regulate essential functions of cells throughout our bodies. The role of FOXOs in the brain is thoroughly integrated with nerve health and is an important area of study that will likely be beneficial for the development of treatments for brain cancers, memory disorders, nerve injuries, and  neurodegenerative diseases. Because research on the role of FOXOs in neurodegenerative pathologies is a relatively new topic, future studies on this subject must generate more general data on FOXO expression mechanisms in PD and AD before attempting FOXO-targeted treatments. By recording and analyzing the behavioral patterns of each individual FOXO isoform in PD and AD, scientists will be able to ascertain what genes, proteins, or hormones future treatments should target. It is possible that one day FOXO activation could be the key to synapse regeneration and neuron regrowth in AD and PD, and individuals may no longer have to fear the loss of their memories and identities. FOXOs might be the final puzzle piece that rescues the minds of people affected by neurodegenerative diseases.

References

  1. Patterson, C. (2018) World Alzheimer Report 2018. Alzheimer’s Disease International2018. https://www.alz.co.uk/research/WorldAlzheimerReport2018.pdf?2
  2. De Lau, L. M. L., Breteler, M. M. B. (2006). Epidemiology of Parkinson’s disease.Neurology, 5 (6), pp. 525-535. doi: https://doi.org/10.1016/S1474- 4422(06)70471-9
  3. Kim, S. Y., Webb, A. E. (2017). Neuronal functions of FOXO/DAF-16. Nutr Healthy Aging 4 (2), pp. 113-126. doi: 10.3233/NHA-160009
  4. Hwang, I., Oh, H., Santo, E., Kim, D. Y., Chen, J. W., Bronson, R. T., Locasale, J. W., Na, Y., Lee, J., Reed, S., Toth, M., Yu, W. H., Muller, F. L., Paik, J. (2018). FOXO protects against age-progressive axonal degeneration. Aging Cell 17 (1), pp. e12701. doi: 10.1111/acel.12701
  5. Santo, E. E., Paik, J. (2018). FOXO in Neural Cells and Diseases of the Nervous System. Curr Top Dev Biol 2018 (127), pp 105-118. doi: 10.1016/bs.ctdb.2017.10.002
  6. Huang, H., Tindall, D. J. (2007). Dynamic FoxO transcription factors. Journal of Cell Science 120, pp, 2479-2487. doi:10.1242/jcs.001222
  7. Salih, D. A. M., Rashid, A J., Colas, D., Torre-Ubieta, L., Zhu, R. P., Morgan, A. A., Santo, E. E., Ucar, D., Devarajan, K., Cole, C. J., Madison, D. V., Shamloo, M., Butte, A. J., Bonni, A., Josselyn, S. A., Brunet, A. (2012). FoxO6 regulates memory consolidation and synaptic function. Genes Dev. 26 (24), pp. 2780-2801. doi: 10.1101/gad.208926.112

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