Compounds for the treatment of Parkinson's disease already exist
LifeSciencesToday based on Johns Hopkins University materials:
Researchers Uncover New Biological Target For Combating Parkinson’s DiseaseJohns Hopkins University scientists have clarified what is happening in the brain in Parkinson's disease and found a compound that mitigates the symptoms of this disease in mice.
Moreover, their findings, described in an article in the journal Nature Neuroscience (Lee et al., Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss), radically change the established ideas about the role of one of the proteins considered the key to the progression of Parkinson's disease.
"We have not only identified the mechanism leading to progressive cell death in both hereditary and non–hereditary forms of Parkinson's disease, but also established that a compound capable of reaching the brain and blocking this process already exists," says Valina Dawson, PhD, director of the stem cell Biology program and neurodegeneration at the Institute for Cell Engineering (ICE) of the Johns Hopkins University School of Medicine. "There are still many challenges to be solved before we get the drug for clinical trials, but the first promising steps have already been taken."
Valina Dawson and her husband Ted Dawson, MD, PhD, director of ICE, have been studying the chain of molecular events leading to the development of Parkinson's disease and have been collaborating in this field for several decades. One of the results of their work is the determination of the function of the Parkin enzyme (Parkin), impaired in Parkinson's disease. As the researchers found out, the function of parkin is to make other proteins intended for destruction visible to cellular recycling mechanisms – to put molecular labels on them. This means that a violation of Parkin's function leads to the accumulation of its target proteins, and the Dawsons, along with other scientists, are studying what role these proteins can play in the development of Parkinson's disease.
Having organized a collaboration with Debbie Swing and Lino Tessarollo from the National Cancer Institute, the Dawsons obtained mice in which the gene encoding the AIMP2 protein can be activated as much as possible. AIMP2 is one of Parkin's target proteins that he marks for destruction, and the genetically modified mice gave scientists the opportunity to ignore the effects of defective parkin and an excess of other proteins and study only the consequences of too much AIMP2.
During aging, mice with overexpression of the AIMP2 gene developed symptoms similar to those of Parkinson's disease. Just like in patients with this neurodegenerative disease, brain cells producing the chemical dopamine died in animals. Since AIMP2 is known for its role in the synthesis of new proteins, scientists concluded that the cause of cell death was a violation of this process. But after studying the synthesis of proteins in the cells of these mice, graduate student Yunjong Lee (Yunjong Lee) did not find any anomalies.
In search of an alternative explanation, Lee tested how cells with excess AIMP2 responded to compounds blocking various cell death pathways, and found that AIMP2 activated the cell self–destruction pathway, parthanatos, discovered by Dawson many years ago. The name of this process is derived from the name of the compound poly (ADP-ribose) (poly (ADP-ribose)), or PAR (PAR), and the Greek word "thanatos" (thanatos), meaning "messenger of death".
In earlier studies, the Dawsons observed activation of partanatos after brain injury or stroke, but not in chronic diseases. However, this study brought other surprises. Lee found that AIMP2 activates parthanatos by direct interaction with the PARP1 protein, which, for a long time, was thought to respond only to DNA damage, but not to signals from other proteins. In fact, AIMP2 is the second discovered protein that activates PARP1, but the idea that PARP1 is involved only in detecting DNA damage and responding to them still firmly holds its position, Valina Dawson notes.
Two cells with excessive production of AIMP2 protein (green) interacting with PARP1 enzyme (red) in cell nuclei. (Photo: Yun-Il Lee/Used with permission from Nature Neuroscience)
Having studied PARP1 for a long time, the Dawsons knew about the development by pharmaceutical companies of compounds designed to block this enzyme. These drugs are used to protect healthy cells in the treatment of cancer and are already undergoing clinical trials. It is very important that two of these compounds are able to overcome the blood-brain barrier, which prevents the effect on brain cells. The Dawsons used one of the compounds blocking PARP1, and Lee tested it on mice with AIMP2 overexpression.
"This compound not only protects dopamine-producing neurons from death, but also prevents the manifestation of behavioral anomalies similar to those observed in Parkinson's disease," Lee comments on the results of his experiment.
Despite the encouraging results, Valina Dawson warns of the existence of many obstacles that must be overcome before any of the brain-reaching compounds will have a chance to conduct clinical trials. Broader preclinical trials are needed, and in mice in which the cause of Parkinson's disease symptoms is not enhanced AIMP2 synthesis. In addition, Dawson explains, in order for trials of any drug for the treatment of Parkinson's disease to be effective, measurable markers of the severity of the disease must be found. Now Ted Dawson and his colleagues from Johns Hopkins University are working on a separate project, the purpose of which is exactly this.
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