Summary: An experimental small molecule helped restore the removal of mitochondria from dopamine-producing neurons in the brain. The findings may help in the development of new therapies for Parkinson’s disease.
Treating mice that have a Parkinson’s disease-causing mutation with a small molecule compound restores the removal of damaged mitochondria from their brain cells, shows a study published today in eLife.
The findings may help explain what goes wrong in dopamine-producing brain cells in people with mutations that cause Parkinson’s disease.
Parkinson’s disease is caused by the progressive loss of brain cells that produce dopamine. This causes the hallmark symptoms of the disease, including tremors, rigid movements, sleep problems and dementia.
“Scientists believe the death of these cells in people with Parkinson’s disease is caused, in part, by the failure of a quality control mechanism that removes damaged energy-producing structures in the cells called mitochondria,” explains first author Francois Singh, Postdoctoral Research Assistant at the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC PPU), University of Dundee, Scotland, UK. “This failure to recycle damaged mitochondria is detrimental to the health of brain cells.”
To learn more, Singh and colleagues teamed up with scientists from the Division of Signal Transduction Therapy, a consortium of academia and pharmaceutical companies. Together they used cutting-edge techniques to observe mitochondria recycling in the brains of mice that have the most common Parkinson’s disease-causing mutation in a gene called LRRK2.
Their experiments showed that damaged mitochondria are not efficiently removed in the animals’ dopamine-producing brain cells, and that damaged components in other types of brain cells are recycled. This may explain why dopamine-producing brain cells are selectively lost in Parkinson’s disease and why the symptoms are all linked to a lack of dopamine.
The mutation in the LRRK2 gene results in the production of a hyperactive version of the protein. Given this, the team treated the mice with a small molecule that inhibits the hyperactive protein and found that it restored mitochondria recycling in the animals’ dopamine-producing brain cells.
The authors say these results are an exciting step forward in the quest to understand mechanisms responsible for this currently incurable disease. These results should help drive and focus research in this area.
“Not only have we discovered new biology, but we have also shown that an LRRK2 inhibitor can rescue a mitochondrial defect related to Parkinson’s disease,” concludes senior author Ian Ganley, MRC Investigator and Scientific Programme Leader at MRC PPU, University of Dundee. “These findings highlight the significant benefit of academic-industrial collaborations that will hopefully accelerate the development of new treatments for Parkinson’s disease.”
About this Parkinson’s disease research news
Contact: Emily Packer – eLife
Image: The image is in the public domain
Original Research: Open access.
“Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice” by Francois Singh, Alan R Prescott, Philippa Rosewell, Graeme Ball, Alastair D Reith, Ian G Ganley . eLife
Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice
Parkinson’s disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation – key features of the autophagy of mitochondria, known as mitophagy.
Here, we investigated the role of LRRK2, a protein kinase frequently mutated in PD, in this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues.
Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice.
This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic Parkinson’s disease, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.