The Cure for Parkinson’s: A Crucial Missing Link?
There are over ten million people with Parkinson's disease worldwide; however, at any point in time, only 2% of people with the disease are below the age of 40.1 Seven years ago, an astonishing observation persuaded many scientists to believe that Parkinson's disease spreads from brain cell to brain cell, like an infection.2 However, little scientific progress was made since this discovery, and much about the spread of the disease remained a mystery, until now. Remarkably, in October 2016, researchers stumbled upon one protein primarily involved in the spread of the disease throughout the brain, and most importantly, how they can stop it.3 Have scientists finally uncovered the final link to a cure for Parkinson’s disease?
This study represents a huge advancement in the scientific field surrounding rare disease research. The increased knowledge surrounding Parkinson’s Disease has created a new potential target for therapies that could not only improve symptoms but potentially modify the course of the disease.1,3,5 It is difficult to receive the diagnosis of Parkinson's disease at any age, but to develop this chronic, neurodegenerative disease at a younger age can be particularly difficult for the child. Young-onset Parkinson disease is characterized by an age of onset between 21 and 45 years, as well as both cognitive and physical symptoms of rigidity, tremors, difficulty with walking and basic motor movements and memory loss.4 Those diagnosed with young-onset Parkinson's disease tend to have additional difficulties as they are dealing with the disease at a much younger age and for a potentially longer period than the typical Parkinson’s disease patient. With many of these patients being parents of young children or beginning new careers, they may not be as equipped to deal with the challenges of this condition.1 Further, young-onset Parkinson's disease presents itself differently from a medical perspective, as the disease causes degeneration in the brain, thereby affecting other developing cognitive functions in adolescents.1
Previous research has discovered that Parkinson's disease causes the destruction of brain function, which distinguishes it from any other movement disorder.1 The exact etiology of young-onset Parkinson disease is still unknown; however, the loss of basic motor function is generally considered to be caused by degeneration of the dopamine-producing neurons in the substantia nigra due to possibly environmental or genetic causes.4 The substantia nigra is a structure in the midbrain that releases the neurotransmitter, dopamine, from its neurons. Dopamine acts as a chemical messenger in the brain between cells and is essential in facilitating basic movement of the body.1 Thus, the loss of neurons in the substantia nigra leads to the loss of dopamine in the brain and the characterized movement disorders associated with the disease.
Current therapies aim to restore dopamine levels and improve symptoms, but these treatment regimens do not improve all symptoms of the disease, nor do they modify the disease process or come without significant side effects.5 Often, the patient is prescribed dopamine, or its precursor, levodopa (L-DOPA).4 However, after five years of treatment with L-DOPA, 30-40% of patients (59-100% by ten years) develop abnormal voluntary movement and motor fluctuations.4-6 For those with young-onset Parkinson's disease, dopamine therapy results in a much more common occurrence of these defective motor side-effects, further decreasing the effectiveness of L-DOPA therapy.1,4 Thus, without any real treatment and a median survival age of 30 years, the patients can only try to mask the symptoms of the quickly progressing disease.4,6
However, in September 2016, researchers at Johns Hopkins University School of Medicine published their most recent discovery, giving new hope to people with young-onset Parkinson’s disease worldwide.3,7 The researchers found that a protein called lymphocyte-activation gene 3 (LAG3) causes Parkinson’s disease development in the brain, and more importantly, they targeted a means of blocking this protein’s action.3,7 The study, published in Science, describes the key findings of their research in which they suggest that an immunotherapy, currently being used in clinical trials as a cancer therapy, could also work to slow the progression of Parkinson’s disease.3 The researchers discovered that, in addition to lowered dopamine, the protein, α-synuclein, plays an important role in brain cell degeneration.3 It is not known as of yet what this protein does in those without the disease, but in those with Parkinson’s, it allows the destructive disease to spread throughout the entire brain.3,7
Previous research discovered that abnormal α-synuclein protein in neurons produces fibrils that damage the brain's function.8 These proteins pass from one neuron to another, spreading across different functional regions of the brain, eventually destroying neurons in all areas of the brain.8 This explains why brain areas responsible for memory and reasoning, as well as those responsible for movement and basic functions, become affected as the disease progresses. The spread of these abnormal proteins was what the study aimed to target. “In looking for ways to slow the progression of Parkinson’s disease, we were interested to see how abnormal α-synuclein enters neurons. Therefore, we began by looking for proteins that would be involved in that process,” said Ted M. Dawson, senior author of the study, in a press release.9
Remarkably, Dawson and his team found that one important protein, LAG3, controls the entry of the damaging particles into the brain cells.3 When mice with Parkinson’s disease lacked LAG3 in the brain cells, the fibrils did not spread throughout the brain, essentially protecting them from the disease.3,7 Therefore, not only did the researchers uncover a way to slow the progression of Parkinson's disease, they found that the inhibition of LAG3 could function as the first real treatment for the disease.3,7,9
As stated by Beth-Anne Sieber, Program Director at the National Institute of Neurological Disorders and Stroke, “This study represents a significant advance in understanding the neurobiological changes underlying Parkinson’s disease. The identification of LAG3 as a mediator in transmitting abnormal α-synuclein between neurons provides both insights into the disease mechanism and a potential therapeutic target for the disease.”9 Dawson and his colleagues are currently testing the LAG3 antibody in animal models of Parkinson’s disease to further explore possible therapeutic and protective effects against the progression of disease symptoms.9 As the disease gradually strips away motor abilities, it leaves its sufferers to deal with the slow degeneration of the control of their bodies. Thus, the findings of this study would not only save millions of lives, but they could also prevent the debilitating motor and cognitive effects of the disease for every person currently suffering and anyone who may suffer from the disease in the future.
1. National Parkinson Foundation: Believe in Better. National Parkinson Foundation. 2016. Available from: http://www.parkinson.org/understanding-parkinsons/what-is-parkinsons/young-onset-parkinsons.
2. E Angot, J Steiner, C Hansen, J-Y Li, P Brundin. Are synucleinopathies prion-like disorders? Lancet Neurol 2010; 9: 1128–38. Available from: doi: http://dx.doi.org/10.1016/S1474-4422(10)70213-1.
3. Mao X, Ou M, Karuppagounder S et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016;353(6307):aah3374-aah3374. doi:10.1126/science.aah3374.
4. RESERVED I. Orphanet: Young onset Parkinson disease. Orphanet. 2016. Available from: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=2828.
5. Olanow CW, et al. Therapeutic prospects for Parkinson disease. Ann Neurol. 2013 Sep;74(3):337-347. Available from: doi: 10.1002/ana.24011.
6. What is Parkinson's Disease? | American Parkinson Disease Association. Apdaparkinsonorg. 2016. Available from: http://www.apdaparkinson.org/parkinsons-disease/understanding-the-basics/.
7. New Immunotherapy May Slow Parkinson's Disease Progression. Immuno-Oncology News. 2016. Available from: https://immuno-oncologynews.com/news-posts/2016/10/06/new-immunotherapy-may-slow-parkinsons-disease-progression/.
8. Masuda-Suzukake M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136:1128-1138. Available from: doi: 10.1093/brain/awt037.
9. Researchers find a gap in the brain’s firewall against Parkinson’s disease. National Institutes of Health (NIH). 2016. Available from: https://www.nih.gov/news-events/news-releases/researchers-find-gap-brains-firewall-against-parkinsons-disease.
Cite This Article:
McKee H., Zheng K., Chan G., Ho J. The Cure for Parkinson's: A Crucial Missing Link? Illustrated by C. Nguyen. Rare Disease Review. January 2017. DOI:10.13140/RG.2.2.35683.14880.