A study by UCLA researchers was published on the online edition of Neurotherapeutics that reported the development of a novel drug that could break down harmful protein groups in Parkinson's disease. Known as the "molecular tweezer," the compound was able to degrade protein aggregates implicated in Parkinson's without interfering with brain activity in zebrafish. Parkinson's disease is a neurodegenerative disorder that affects the central nervous system, which is comprised of the brain and spinal cord. A neurodegenerative disorder is one that is caused by the death of a component of the nervous system. In the case of Parkinson's disease, cells in a part of our brain called the "substantia nigra" are killed.
These cells are responsible for producing a hormone called dopamine, which facilitates our control over our bodily movements. Parkinson's patients are typically characterized with uncontrolled, erratic bodily movements.
More than thirty known diseases, including Parkinson's, Alzheimer's and Type 2 diabetes are caused by an aggregation or "clumping" of proteins, which collectively become harmful to the body. In Parkinson's, the protein responsible for the onset of the disease is "alpha-synuclein," which is found in all Parkinson's patients. The aggregates of alpha-synuclein, called Lewy bodies, ultimately kill the neurons in the brain that are responsible for dopamine production.
It is difficult to design drugs to target the aggregate of proteins, especially for Parkinson's, because alpha-synuclein is ubiquitous in the brain. However, the new drug that the UCLA study reported is called CLR01, which acts as a molecular tweezer to "tweeze" off alpha-synuclein units from their masses.
The compound is shaped like a C and wraps around groups of lysine, a type of amino acid with a positive charge found on many proteins. The researchers discovered that the molecular tweezers are able to isolate alpha-synuclein and prevent them from forming aggregates. The isolated proteins are harmless to the brain's neurons.
Surprisingly, CLR01, which has the ability to bind to many different compounds, was able to undergo process-specific mechanisms to specifically bind to alpha-synuclein. No other proteins in the brain were affected, making CLR01 a very attractive option with which to perform further research, as it avoids complications of side effects.
After using cell cultures to test CLR01 effectiveness, animal models were used to further legitimize the drug usage. Zebrafish were chosen as animal models because they are easy to genetically manipulate, they develop rapidly, and are transparent, allowing for easier observation. CLR01 demonstrated effectiveness in preventing aggregation of alpha-synuclein, eventually stopping the progression of Parkinson's in the transgenic zebrafish.
In a previous study by UCLA researchers, CLR01 was found to have profound therapeutic effects on two brain lesions in Alzheimer's patients, the amyloid plaques and neurofibrillary tangles.
CLR01 was able to block amyloid beta proteins from aggregating, which inhibited the development of amyloid plaques, the known culprit of causing Alzheimer's. Additionally, the compound blocked tau proteins from aggregating into neurofibrillary tangles, another deposit of proteins that is known to lead to Alzheimer's. The effects of CLR01 were particularly concentrated in the hippocampus of the brain, where our storage of memories resides.
No treatment has been found for Parkinson's patients. Although drugs can alleviate symptoms, nothing has been effective towards slowing the progression of the disease.
However, CLR01, which showed no side effects, has promising results for prospective drugs that can be administered for Parkinson's patients. A mouse model study is now underway for further research.
