Maybe you’ve seen the movie “Awakenings.” This film is based on the book by neurologist Oliver Sacks, who tells how he manages to temporarily restore “freedom” to his patients paralyzed by parkinsonism.
Motionless and absent for decades, he decides to treat them with what was considered a miraculous experimental drug: Levodopa (L-dopa), which stimulates the body to produce dopamine.
Unfortunately, most patients began experiencing adverse effects from L-dopa months later, such as tics, involuntary movements, and emotional instability. By stopping the drug, the patients returned to the states they were in before the treatment.
The origin of the disease in the brain
This movie reflects historically how difficult it has been to treat Parkinson’s disease. Now what is Parkinson’s disease? It is a neurodegenerative pathology characterized by the loss of neurons in a region of the brain called black substance. It is located in the midbrain, this being one of the places where dopamine is generated, a neurotransmitter that allows communication between neurons and is necessary to modulate movement and muscle tone.
As the disease progresses, symptoms that are not directly related to movement appear, including psychosis (a disorder characterized by disconnection with reality) and dementia (a syndrome that involves impaired memory, intellect and behavior), which aggravate the patient’s disability.
One characteristic, common in all people who suffer from this disease, is the presence of a substance that alters the proper functioning of neurons and that occurs in the form of clusters of a protein known as alpha-synuclein; the accumulation of these proteins generates the so-called Lewy bodies that are observed inside neurons by means of immunostaining techniques (staining of the cell through the use of labeled antibodies), this deposit generates toxicity, causing cell death.
Parkinson’s disease affects more than 10 million people around the world. In Chile, according to the Minsal there are about 40 thousand patients with this diagnosis. In turn, this disease is incorporated into the government’s program of Explicit Guarantees in Health (GES), where it considers a set of medical benefits that includes the delivery of drugs to treat the symptoms of the disease.
New possible cures
In recent years, numerous drug treatments, surgery, and gene therapies have been developed that substantially improve the quality of life of patients affected by Parkinson’s disease. Likewise, there has been a growing interest in groups of researchers to develop a possible cure for this pathology.
Among the new gene therapies, there are antisense oligonucleotides, molecules that make up the genetic material and, in this therapy, short sequences of these molecules are elaborated, which are used to alter the function of the cell or prevent it from making a protein in particular.
Since some molecules of genetic material are composed of two strands that are joined opposite each other in the opposite direction, antisense fibers are used in this therapy, which is why the therapy is called that. Its use has been authorized by the Food and Drug Administration (FDA) and has already been administered in spinal muscular atrophy, a genetic disease that affects motor neurons (which transmit instructions on movement to muscles) of the spinal cord and in clinical trials for other neurological conditions.
On the other hand, in a study published in 2019 and carried out by researchers from the University of Osaka, in Japan, they used the same technique, with some modifications. In this case, a Parkinson’s mouse model expressing human-type alpha-synuclein was used. The antisense oligonucleotides were injected into a specific area in the brain, obtaining a 24.5% reduction in alpha-synuclein protein expression. At the behavioral level, improvements in motor performance were observed in those mice that showed a decrease in the expression of said protein.
A more recent study, led by Hao Quian and his team from the University of California, published in June 2020 in the journal Nature, demonstrated in sections of neuronal tissue from mice and human fetuses, that the injection of antisense oligonucleotides can generate that a type of cells in the nervous system, called astrocytes (glial cells), transform into neurons, both in the black substance as in two other areas of the brain.
What is interesting is that, by causing injury to the black substance Through chemical methods, on one side of the mouse brain, the death of the dopaminergic neurons in said area was generated, which was reversed when using the technique that incorporates antisense oligonucleotides, thus being able to generate the appearance of new dopaminergic neurons on the injured side.
The researchers of this study concluded that, in a mouse model of Parkinson’s disease (caused by injury to the black substance), dopamine levels were restored because the new neurons were able to generate the neurotransmitter at levels similar to those in the uninjured area.
In addition to responding to an external electrical stimulus (an electrode that carries an electrical pulse and allows the depolarization of the neuron) and to different neurotransmitters, such as Glutamate and GABA, substances that allow communication between neurons, in this case, it allowed to conclude that the new neurons dopaminergic cells communicate with other types of neurons (cells that make other types of neurotransmitters).
Finally, by evaluating three behavioral tests that consisted of rotations and use of their limbs where they compared the motor responses of the injured and the uninjured side, it was observed that the motor deficits caused by the injury were corrected, observing results similar to those on the uninjured side, that is, these new dopaminergic neurons eliminate the motor symptoms caused by this Parkinson’s model.
Although the results of these three studies are very promising, the therapy certainly requires further investigation, but it does shed light that in the future it will be possible to treat and / or reverse Parkinson’s disease, either in the initial or advanced stages, having the potential to dramatically improve the quality of life of people who suffer from it. Even so, there is a long way to go to reach preclinical and clinical studies that allow the use of these alternatives in people with the disease.
Article 2017: https://cell.com/molecular-therapy-family/nucleic-acids/retrieve/pii/S2162253117302287?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2162253117302287%3Fshowall%3Dtrue
Article 2019: https://www.nature.com/articles/s41598-019-43772-9
Article 2020: https://www.nature.com/articles/s41586-020-2388-4
* This article arises from the agreement with the Interdisciplinary Center of Neuroscience of the University of Valparaíso.