Parkinson’s disease: a diagnosis
that marks the beginning of end of a patient’s motor functions. It is the most
common of the neurodegenerative diseases, and in terms of treatment, also
happens to be the most elusive. The disease is characterized by the unexplained
death of dopaminergic neurons in the substantia nigra (SN) portion of the
brain. Dopamine is vital for control of motor function, thus the death of these
neurons begins the start of the disease. Thus far, we have only learned how to
treat the symptoms of the disease. Patients are treated with Levodopa, a
precursor to dopamine, coupled with carbidopa to ensure its safe delivery to
the brain and even distribution to the central nervous system.
Patients diagnosed with
Parkinson’s disease will experience resting tremors (especially in the hands),
bradykinsesia (slowness of movements), limb rigidity, and gait and balance
issues. In addition to motor function loss, there are non-motor symptoms as
well. These include, but are not limited to: depression, loss of sense of
smell, and cognitive impairment.
Molecular causes of the disease
are largely unknown. Only 10-15% of cases can be attributed to genetics, while
the remaining are sporadic with no known cause. There are currently one million
people in the United States living with PD. Because of the late onset of
symptoms, the majority of cases are only caught when the symptoms have begun
and the patient’s motor function is already degenerating, they are already late
stage patients. This gives doctors and PD researchers no time to focus on
prevention or see what exactly is causing it.
Nilotinib, advertised as Tasigna, is currently
approved for treating newly diagnosed adult patients
with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in
chronic phase (CP). Studies have shown that Nilotinib decreases levels of
alpha-synuclein in the brain as well as the blood. The primary component of the
Lewy Bodies found in the substantia nigra, the site of this neuron death, is
alpha-synuclein. Alpha-synuclein activates Abl, a tyrosine kinase that has many
functions, including apoptosis. In trials with mice, the drug was found
to not only increase dopaminergic levels and improve motor function, but also
to clear cytosolic debris in SN neurons.
Is Nilotinib scraping the surface of new treatment
options for Parkinson’s? Are we finally understanding the molecular events that
lead up to this devastating neurodegenerative disease?
Resources
Dauer, W., & Przedborski, S. (2003). Parkinson’s Disease:
Mechanisms and Models. Neuron,
39, 889-909.
Retrieved November 16, 2017.
Hebron, M. L., Lonskaya, I., & Moussa, C. E. (2013). Nilotinib
reverses loss of dopamine
neurons and improves
motor behavior via autophagic degradation of -synuclein in
Parkinsons disease
models. Human Molecular Genetics, 22(16), 3315-3328.
doi:10.1093/hmg/ddt192
Karuppagounder, S. S., Brahmachari, S., Lee, Y., Dawson, V. L.,
Dawson, T. M., & Ko, H. S.
(2014). The c-Abl
inhibitor, Nilotinib, protects dopaminergic neurons in a preclinical
animal model of
Parkinsons disease. Scientific Reports, 4(1).
doi:10.1038/srep04874
Pagan, F., Hebron, M., Valadez, E. H., Torres-Yaghi, Y., Huang,
X., Mills, R. R., . . . Moussa, C.
(2016). Nilotinib
Effects in Parkinson’s Disease and Dementia with Lewy Bodies.
Journal of
Parkinson's Disease,6, 503-517. Retrieved November 15, 2017.
Parkinson Disease Treatment & Management. (2017, November 15).
Retrieved November 16,
Tasigna. (n.d.). Retrieved November 16, 2017, from https://www.hcp.novartis.com/products/ta
What Is Parkinson's? (2017, October 18). Retrieved November 16,
2017, from http://www.parkinson.org/understanding-parkinsons/what-is-parkinsons
By Savannah Tucker, Bachelor of Public Health Student, University of Kentucky
By Savannah Tucker, Bachelor of Public Health Student, University of Kentucky
This is a very interesting topic. I am to know what are the long term effects of this newly synthesized medicine. With further researcher hopefully there will be a cure to PD.
ReplyDeleteNeurodegenerative diseases are some of the worst diseases we are dealing with in the society. It is very hard to understand the nervous system and because everyone's nervous system differs from one another it makes it very difficult to find similarities amongst all patients and it makes it very difficult for researchers to identify the cause of PD. I really hope with more research we will figure out the causes of all neurodegenerative diseases some day.
ReplyDeleteThis is a very interesting blog and an important topic. I actually knew someone with Parkinson's disease and it was sad to see her deteriorate the way that she did. Is this the only drug that has been approved for use and if so are there any others that are in the trial/research stages? Im sure this is a very difficult disease to handle/treat because of the system it impacts. However, I am glad they are continuing to do work to treat it.
ReplyDeleteYes this is very devastating disease, my Grand father had it. As i mentioned in class, Monoclonal antibodies against alpha-synuclein is currently in trial.
DeleteWith dopamine being a key player in the development and progression of this neurodegenerative disease, I wonder how endocrinologists are responding to Parkinson's disease and if any collaborations can/have been made to better explore this relationship. I know that with any hormone signaling pathway that regulation can be in part governed by receptors for these neurotransmitter hormones, but also by circulating levels. I know that neurogenesis and neuroplasticity is a more difficult hurdle to tackle, but in knowing how these endocrine mechanisms work I wonder if there is a potential for preventative measures of disease development in addition to current efforts to treat Parkinson's.
ReplyDeleteOne of the problem is that brain cells producing dopamine is dying so unfortunately high amount of stimulating hormone wont help. Also endocrine works systemically (though blood) this means it will all organs and not just brain.
DeleteI agree, that dopamine precursors and dopamine agonist simply cure the symptoms. And i do believe alpha synuclein accumulation is what causing the problem. Removal or preventing the accumulation seems like the only way to treat PD.
ReplyDeleteHopefully this drug will get further testing to understand whether or not it could advance the treatment for Parkinson's Disease! Neurodegenerative diseases are difficult to deal with, and any progress is a great step forward for the neuro community.
ReplyDeleteAlways an interesting topic to discuss! It is important for current and future research to look at genetic factors that could lead to PD, and alpha-synuclein aggregation seems to be a favorite. That is great, but I'm not sure that reducing alpha-synuclein in patients that already have PD would have a great effect in humans. I do think that if given at an early stage of PD (maybe with patients who show non-motor symptoms and have yet to show motor symptoms) it could be effective. I'm excited to see where this goes as studies progress.
ReplyDeleteSome examples of non-motor (premotor) symptoms associated with PD: Impaired olfaction, sleep disturbances, constipation (microbiome?), and depression. These may seem like common things, but it is pretty rare to see these presented together.
DeleteIt will be interesting to see what direction we take in the fight against Parkinson's Disease. I hope that we will find a way to do more than simply treat symptoms. But it is good to see that progress is being made to find some relief for those suffering from the disease.
ReplyDeleteI think all brain disorders are so interesting because we can't seem to figure out exactly what they are or how they work. I hope this drug can help to treat some Parkinson's disease patients as we continue to look for a way to cure the disease.
ReplyDeletei hope the drug gets more time and chances to test the benefits on Parkinsons since it effects many people
ReplyDeleteThis was a good case study on PD. Hopefully the drug will be tested on more and they will be able to provide a better understanding of the drugs and PD.
ReplyDeleteAman Patel - I found interesting the that drug was actually being tested for another disorder but happened to find positive effects that might help patients with parkinson's
ReplyDeleteIn the intro to neuroscience class I am taking we talked briefly about a treatment University of Kentucky researchers actually worked on, using the glial derived neurotropic factor (GDNF) gene. GDNF therapy has been shown to aid re-growth of dopaminergic neurons associated with motor nerve function in the SN. Drug companies decided to go back to the drawing board on it because of severe, life threatening side effects in some of the patients. 60 minutes did a story on this back in 2005 on a particular person that had amazing success with the treatment.
ReplyDelete