First described as “shaking palsy,” Parkinson’s disease is characterized by the loss of both motor features and non-motor features. This widespread disease impairs the quality of life of patients as well as their families and caregivers as the neurodegenerative disease progresses (1). The loss of midbrain neurons of the substantia nigra causes dopamine levels in the brain to diminish, ultimately resulting in cognitive changes, muscular rigidity, and resting tremor (2).
There is currently no cure for Parkinson’s disease because of the neurodegeneration that occurs as the substantia nigra of the midbrain is lost. There is an urgent need for treatments that are more effective in combating debilitating and devastating diseases that involve neurodegeneration. Neurodegenerative diseases are becoming more prevalent as the elderly population is increasing, thereby stressing the urgency of the need of an effective therapeutic agent (3). The etiology of the disease is not yet understood, and treatments such as L-dopa therapy work only to control motor function without changing the progression of the disease.
L-Dopa therapy has proven successful in Parkinsonian patients by using the L-dopa and dopamine agonists, or chemicals that bind to receptors, to enhance signal messaging between neurons. L-dopa (or levodopa) is converted to dopamine in the brain. Since therapies for Parkinson’s disease often span long periods of time, side effects that arise from this treatment include increased toxicity and inflammatory response, causing patients to undergo an abundance of monitoring (4). In the long run, this treatment is the most effective one available to Parkinson’s disease patients although it stops being effective only after a few years. DNA methylation, a process in which gene transcription is typically abridged by adding a methyl group to a DNA molecule, reduces the effectiveness of L-dopa and the therapy instead gives rise to involuntary spasmodic movements known as dyskinesia (5). The adverse effects of this therapy as well as other Parkinson’s treatments may be very problematic.
A study done by Xiang-Dong Fu at the University of California San Diego School of Medicine focuses on preventing neuronal loss rather than modifying the outcomes of it. He was able to protect vulnerable neuronal circuits in the brain formed by the neurons and replace the lost neurons. These new neurons would then be able to reconstruct the disrupted areas. This novel finding may be monumental in reconstructing damaged parts of the brain in neurodegenerative diseases (6).
The adaptability of the mouse brain has been utilized to produce new neurons that prove to be advantageous in disease models. Transcription factors are involved in converting DNA to RNA. PTB and nPTB are two lineage specific transcription factors that are used for programming cells in animal models. The transcription factors also play a role in regulating neuronal development. Most importantly, they play a role in the transformation of mouse and human fibroblasts (connective tissue cells) to functional neurons. (7).
The researchers were able to insert an antisense oligonucleotide sequence in a noninfectious virus. This designed piece of DNA would then bind specifically to the region of RNA coding for PTB and the region would be degraded. The PTB sequence, in return, would not be translated into functional PTB. This progressive conversion would improve neuronal development. Antisense nucleotides are essentially artificial pieces of DNA that are at the forefront of contributing to neurodegenerative diseases (8). In addition, astrocytes from different parts of the brain will convert into different neuronal subtypes. The depletion of PTB is able to cause isolated mouse and human astrocytes to convert into functional neurons that are then able to innervate neuronal circuits. In mice, the astrocytes taken from the midbrain were chemically induced to transform into dopaminergic neurons (6). Dopamine levels are then restored and motor deficits are remedied, much like in the case of transiently suppressing PTB with antisense oligonucleotides.
This one-step, efficient, and feasible process may replace neurons in neurodegeneration. This process is powerful in that it would be the first to restore the function disturbed neuronal circuits and actually reverse neurodegenerative processes. This groundbreaking discovery has the potential of changing the lives of many patients awaiting treatment.
References:
1. Kleiner-Fisman, G., Stern, M. B., & Fisman, D. N. (2010). Health-Related Quality of Life in Parkinson disease: Correlation between Health Utilities Index III and Unified Parkinson's Disease Rating Scale (UPDRS) in U.S. male veterans. Health and Quality of Life Outcomes, 8(1), 91. doi:10.1186/1477-7525-8-91
2. Hedlund, E., Pruszak, J., Lardaro, T., Ludwig, W., Viñuela, A., Kim, K., & Isacson, O. (2008). Embryonic Stem Cell-Derived Pitx3-Enhanced Green Fluorescent Protein Midbrain Dopamine Neurons Survive Enrichment by Fluorescence-Activated Cell Sorting and Function in an Animal Model of Parkinson's Disease. Stem Cells, 26(6), 1526-1536. doi:10.1634/stemcells.2007-0996
3. Fahn, S. (2008). Clinical Aspects of Parkinson Disease. Parkinson's Disease, 1-8. doi:10.1016/b978-0-12-374028-1.00001-4
4. Levin, O. S. (2017). Long-Term Dopaminergic Therapy Of Parkinson Disease. Medical Council, (10), 74-80. doi:10.21518/2079-701x-2017-10-74-80
5. Cenci, M. A. (2014). Presynaptic Mechanisms of l-DOPA-Induced Dyskinesia: The Findings, the Debate, and the Therapeutic Implications. Frontiers in Neurology, 5. doi:10.3389/fneur.2014.00242
6. Qian, H., Kang, X., Hu, J., Zhang, D., Liang, Z., Meng, F., . . . Fu, X. (2020). Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature, 582(7813), 550-556. doi:10.1038/s41586-020-2388-4
7.One-time treatment generates new neurons, eliminates Parkinson's disease in mice. (2020, June 25). Retrieved June 25, 2020, from https://www.sciencedaily.com/releases/2020/06/200625102540.htm
8.Williams, R. (n.d.). Astrocyte-to-Neuron Method Reverses Neurodegeneration in Mice. Retrieved June 25, 2020, from https://www.the-scientist.com/news-opinion/astrocyte-to-neuron-method-reverses-neurodegeneration-in-mice-67661?_hsmi=90218290