Parkinson's: Mutant gene interaction may pave the way for new treatments

New research finds that an interaction between a mutant gene and an abundant brain protein shows similarities with clinical indicators of Parkinson’s disease. These findings could lead to new treatments for the disease.
[Parkinson's and genetics puzzle]
Inhibiting the activity of the LRKK2 gene mutation “may slow progression of Parkinson’s disease-associated pathology.”

Parkinson’s disease (PD) is a progressive neurological disease that affects around 60,000 Americans every year. Its symptoms can be life-changing and include a general slowness of movement, tremors, and rigidity, although symptoms differ from person to person.

Drugs and therapies can help to manage the condition, but there is currently no known cure.

Researchers at the University of Alabama at Birmingham (UAB) have discovered what could be a significant finding in the path to developing a cure for PD.

Although it is thought that environmental factors cause many cases of PD, the disease can also develop through genetic factors. Several genetic factors have been shown to increase a person’s risk of developing Parkinson’s disease, although exactly how these make some people more susceptible to the condition has previously been unclear.

The most common genetic cause of Parkinson’s disease is a mutation in a gene called leucine-rich repeat kinase 2 (LRRK2).

Preclinical drugs block mutant gene, slow Parkinson’s progress

The research team found that the mutated LRKK2 gene causes inclusions, or abnormal structures, within the neurons of the brain. These inclusions are made of a protein called alpha-synuclein, which are found in the brains of people with PD after death.

It was found that in in-vitro tests, small, potent concentrations of preclinical drugs that inhibit the mutant variant of the LRKK2 gene reduced the formation of the alpha-synuclein inclusions.

The study, published in Journal of Neuroscience, suggests that the interaction between mutant LRRK2 kinase and alpha-synuclein “may uncover new mechanisms and targets for neuroprotection.”

The authors write: “These results demonstrate that alpha-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of Parkinson’s disease-associated pathology.”

Laura A. Volpicelli-Daley, Ph.D., and Andrew B. West, Ph.D. led the research team at the Center for Neurodegeneration and Experimental Therapeutics, of the UAB Department of Neurology.

LRRK2 kinase inhibitors: Promising treatment for Parkinson’s

Volpicelli-Daley and colleagues note that the potential clinical applications for these LRRK2-associated neuroprotection strategies require testing in other preclinical models of Parkinson’s disease.

“These data give us hope for the clinical potential of LRRK2 kinase inhibitors as effective therapies for Parkinson’s disease. The LRRK2 kinase inhibitors may inhibit the spread of pathologic alpha-synuclein, not only in patients with LRRK2 mutations, but in all Parkinson’s disease patients. Future studies to validate the safety and efficacy of the LRRK2 inhibitors will be necessary before testing the inhibitors in human clinical trials.”

Laura A. Volpicelli-Daley, Ph.D.

Alpha-synuclein also plays a role in the development of dementia and is linked with Alzheimer’s disease and other neurodegenerative disorders.

Volpicelli-Daley applied low concentrations of pre-formed fibrils of alpha-synuclein to neurons to cause modifications associated with PD. This model was used to test the effects of the mutant LRRK2 kinase, G2019S-LRRK2, on the formation of inclusions.

Another key finding from the study was that G2019S-LRRK2 enhanced alpha-synuclein inclusion formation in dopamine neurons in a part of the brain called the substantia nigra pars compacta.

This area of the brain dies in people with PD, and so this observation confirms a link between the G2019S-LRRK2 mutation and PD pathogenesis.

The researchers indicate that the G2019S-LRRK2 mutation may increase the risk of PD by boosting the amounts of mobile – as opposed to membrane-bound – alpha-synuclein in neurons.

It is hoped that these findings will shape future research into the causes of the disease and the LRKK2-inhibiting drugs.

Read about research that challenges the cause of PD.

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