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A Breakthrough In Parkinson's Disease Research

Release time:2022/1/18 9:38:07
Author:Huateng Pharma

Parkinsons disease is the second most common neurodegenerative disease after Alzheimers disease, affecting the health of …

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease, affecting the health of millions of people. Research over the past few decades has pointed out that the loss of dopamine-releasing neurons in the brains of people with Parkinson's disease, leading to the disruption of the motor functions regulated by these neurons, resulting in slowness of movement, stiffness, uncontrollable tremors and other motor disorders.  

Levodopa is a drug commonly used to replace dopamine and help patients with Parkinson's disease reduce symptoms. Over time, however, levodopa becomes less effective, making it particularly difficult to treat people with advanced Parkinson's disease.

 parkinsons disease.jpg

On November 3, 2021, a preclinical study was published in the leading academic journal Nature, opening the door to new treatments for patients with advanced Parkinson's disease.

In this new study, researchers at Northwestern University uncovered a new mechanism by which Parkinson's disease causes dyskinesia and designed a gene therapy based on the discovery of the new mechanism to help improve the effectiveness of levodopa in advanced Parkinson's disease.

In previous studies, it was found that a small area of the brain called the substantia nigra, where dopamine-releasing neurons are the first to be damaged in Parkinson's disease. In these neurons, the researchers also noticed a feature of mitochondrial damage.

Mitochondria are the power plants of the cell, an organelle essential for energy production. However, whether mitochondrial damage is a cause or a consequence of Parkinson's disease has long been debated. According to neuroscientist Professor James Surmeier, clarifying this question is critical to developing effective treatments. If mitochondrial damage proves to be the cause of the disease, then finding ways to preserve mitochondrial function could potentially slow or stop the progression of Parkinson's disease.


Mitochondria are important power plants for cells to produce energy

To answer the above controversy, Surmeier's research team used advanced genetic tools to construct a new genetically engineered mouse that interferes with mitochondrial complex I function in dopaminergic neurons, causing mitochondrial metabolism problems in these neurons.  As the“power plant” shuts down, these cells lack enough energy and eventually burn out and die.  

However, the researchers found that after mitochondrial damage, these neurons unexpectedly remained intact for a relatively long time. Initially, these neurons extend to the axons of the adjacent brain region known as the striatum to reduce dopamine release.  Dopamine loss in the striatum has long been considered the sole cause of dyskinesia in Parkinson's disease. However, experiments showed that reduced dopamine in the striatum alone was not enough to cause dyskinesia associated with Parkinson's disease.

The researchers observed that these neurons in mice actually also released dopamine through the soma and dendrites at the substantia nigra to maintain specific motor functions. After a few months, the nerve cells release less and less dopamine to the substantia nigra, and eventually, the axons degenerate and the cells slowly die. At the same time, the mice exhibited movement disorders typical of advanced Parkinson's disease in humans.

Mitochondrial damage.jpg

Mitochondrial damage causes neurons in the substantia nigra to gradually reduce the release of dopamine
(Image source: Reference [2])

Based on the results of the above experiments, the researchers summarize their two important findings: impaired mitochondrial function is sufficient to contribute to the development of Parkinson's disease, and that the substantia nigra loses its function to release dopamine is key to the development of dyskinesia.

These new findings give scientists a new therapeutic target: replenishing dopamine in the substantia nigra. The researchers designed a gene therapy that targets the substantia nigra, enabling cells there to convert levodopa into available dopamine. Proof-of-concept experiments in mice showed that the therapy effectively enhanced the therapeutic effects of levodopa in the advanced stages of Parkinson's disease.

Prof. Surmeier commented that they hope that the new model of Parkinson's disease based on mitochondrial disorders can help them develop new tests that can diagnose Parkinson's disease patients 5 to 10 years in advance, so that treatment can be started as early as possible, and ultimately help patients change the progress of the disease.

Pramipexole is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It was approved for medical use in the United States in 1997. Huateng Pharma is a leading pharmaceutical API & Intermediates manufacturer in China, which can provide intermediates of Pramipexole with capacity from grams to kilograms, such as CAS NO.:106092-11-9, CAS NO.:27514-08-5, CAS NO.:106092-09-5 and CAS NO.:104617-49-4. 



[1] Disruption of mitochondrial complex I induces progressive parkinsonism.

[2] Mice with disrupted mitochondria used to model Parkinsons disease 

[3] Gene therapy boosts Parkinsons disease drug benefits.