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The study of Parkinson’s disease has persisted for over two centuries. Discovered in 1817 by James Parkinson, the tricky nature of the neurodegenerative disease attracted the fascination of many researchers and physicians (1). The Parkinson’s Foundation explains that the disease is characterized by the loss of dopamine-producing (dopaminergic) neurons in the midbrain structure called the substantia nigra (2). The loss of dopaminergic neurons disrupts the nigrostriatal circuit, a dopamine pathway involved in motor planning. This disruption leads to motor deficits, often manifesting in the “four cardinal signs of Parkinson’s” — pill rolling tremors, slowness of movement, limb rigidity and balance problems (3). Though the disease itself is not fatal, complications due to the resulting symptoms can cause death; the CDC reports Parkinson’s disease as the 14th leading cause of death in the United States (4). 

Parkinson’s disease is considered incurable, as there are currently no methods to stop or restore dopaminergic neuron loss. Treatment methods instead focus on slowing the neuron decline and controlling symptoms. Medication, lifestyle changes and, in serious cases, surgery are often advised by physicians (5). 

As Parkinson’s progresses and symptoms worsen, most physicians opt to use Levodopa (commonly known as L-dopa) medication. A few key details make L-dopa an ideal course of treatment. First, L-dopa serves as a precursor to dopamine (8). By providing L-dopa as a building block for dopamine, physicians address the dopamine deficit. Second, L-dopa is an amino acid (9). Amino acids are able to pass through the highly selective blood-brain barrier, unlike neurotransmitters like dopamine. L-dopa’s amino acid status grants access through the barrier, making L-dopa treatment possible. 

Unfortunately, L-dopa treatment has many drawbacks. Patients often complain of side effects such as nausea, dizziness, headaches and intense drowsiness, in addition to several more serious side effects such as central nervous system problems and greater risk for hip fractures (8). Additionally, L-dopa treatment makes patients dependent on continual treatment, as withdrawal or reduction can cause neuroleptic malignant syndrome, a complication that drastically reduces quality of life. These drawbacks illustrate the need for a new standard treatment for Parkinson’s patients. 

Thankfully, new research suggests a potential breakthrough in Parkinson’s disease treatment. Neuroscience researchers in California may have found a method to restore neurons lost due to Parkinson’s disease. Hao Qian’s team at University of California-San Diego published their research in the scientific journal Nature, where they outlined their simple method of neuronal restoration (6). In a chemically-induced model of Parkinson’s disease in mice, the researchers replaced lost dopaminergic neurons by converting brain cells called glial cells (specifically astrocytes) into functional neurons. The researchers observed that the depletion of the RNA-binding protein PTB in astrocytes removed from mouse brains triggered astrocyte-to-neuron conversion. Using that observation, the researchers hypothesized a similar result for astrocytes inside mouse brains. In the mouse brains, the researchers degraded the messenger RNA that codes for PTB. The following observations confirmed their hypothesis; the single step of PTB depletion can catalyze astrocyte-to-neuron conversion. 

The research conducted by the California team is further corroborated by an earlier study published in the scientific journal Cell in April 2020. Haibo Zhou’s team at the University of Chinese Academy of Sciences degraded messenger RNA using an alternate method, and again observed the conversion of glial cells to neurons (7). The parallel findings of Zhou’s team provide compelling evidence that astrocyte-to-neuron conversion can be stimulated by PTB depletion. 

The implications of such research on Parkinson’s disease are considerable. The ability to restore dopaminergic neurons through the researchers’ methods shows promise for reinnervating the nigrostriatal circuit, as the newly converted neurons can populate the substantia nigra and striatum. The reestablishment of the nigrostriatal circuit could potentially restore motor deficits, meaning debilitating Parkinson’s symptoms may be alleviated. It is important to note, however, that the research conducted by both Qian’s team and Zhou’s team were in mouse models, not the human brain. 

Future clinical research is necessary to determine the viability of astrocyte-to-neuron conversion in human patients. These clinical trials would likely consist of local application of a virus responsible for PTB depletion. Success in these clinical trials would require proof of valid astrocyte-to-neuron conversion, proof of long-term stability in converted cells and proof of the approach’s safety to surrounding cells (10). 

Parkinson’s disease remains incurable, but the research surrounding astrocyte-to-neuron conversion holds promise as an exciting potential pathway for treating neurodegeneration in Parkinson’s patients. 

 

References:

  1. Goetz, Christopher. The History of Parkinson’s Disease: Early Clinical Descriptions and Neurological Therapies. Cold Spring Harbor Perspectives in Medicine. 1 Sep. 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234454/#:~:text=Defining%20Parkinson's%20Disease,earlier%20descriptions%20(Parkinson%201817).
  2. Elkouzi, Ahmad. What is Parkinson’s? Parkinson’s Foundation. https://www.parkinson.org/understanding-parkinsons/what-is-parkinsons
  3. Jankovic, J. Parkinson’s disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery and Psychiatry. 2008. Vol.79. Issue 4.  https://jnnp.bmj.com/content/79/4/368.short
  4. Kochanek, Kenneth et al. Deaths: Final Data for 2017. National Vital Statistics Reports. 2019. Vol. 68. No. 9. CDC. 
  5. Parkinson’s disease. Mayo Clinic. 30 June 2018. https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/diagnosis-treatment/drc-20376062
  6. Qian, Hao et al. Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature. 24 June 2020. https://www.nature.com/articles/s41586-020-2388-4#citeas
  7. Zhou et al. Glia-to-neuron Conversion by CRISPR-CasRx Alleviates the Symptoms of Neurological Disease in Mice. Cell. 30 April 2020. https://www.sciencedirect.com/science/article/abs/pii/S0092867420302865
  8. Ghandi, Kavita. Saadabadi, Abdolreza. Levodopa (L-Dopa). National Institute of Health. 23 April 2020. https://www.ncbi.nlm.nih.gov/books/NBK482140/
  9. Gregory, SIan and Burnham, Paul. Dopamine. Hillsborough College. October 2008. http://www.chm.bris.ac.uk/motm/dopamine/dopamineh.htm#:~:text=The%20most%20common%20treatment%20used,safely%20transported%20across%20the%20interface.
  10. Arenas, Ernest. Method to combat Parkinson’s disease by astrocyte-to-neuron conversion. Nature. 24 June 2020. https://www.nature.com/articles/d41586-020-01817-4