Findings identify opportunities for new treatments of Parkinson’s and related neurodegenerative disorders
A longstanding mystery in Parkinson’s disease (PD) research has been why some individuals carrying pathogenic variants that increase their risk of PD go on to develop the disease, while others who also carry such variants do not. The prevailing theory has suggested additional genetic factors may play a role.
To address this question, a new Northwestern Medicine study published in the journal Science used modern technology, called CRISPR interference, to systematically examine every gene in the human genome. The scientists identified a new set of genes that contribute to the risk of PD, which opens the door to previously untapped drug targets for treating PD.
More than 10 million people worldwide are living with PD, the second-most common neurodegenerative disease after Alzheimer’s disease.
“Our study reveals that a combination of genetic factors plays a role in the manifestation of diseases like Parkinson’s disease, which means that therapeutic targeting of several key pathways will have to be considered for such disorders,” said corresponding author Dimitri Krainc, MD, PhD, the chair and Aaron Montgomery Ward Professor of Neurology and director of the Feinberg Neuroscience Institute.
“It also is possible to identify such genetic factors in susceptible individuals by studying tens of thousands of patients, which is challenging and costly,” Krainc said. “Instead, we used a genome-wide CRISPR interference screen to silence each of the protein-coding human genes in cells and identified those important for PD pathogenesis.”
Variants in Commander genes contribute to PD
The study discovered that a group of 16 proteins, called Commander, comes together to play a previously unrecognized role in delivering specific proteins to the lysosome, a part of the cell that acts like a recycling center, breaking down waste materials, old cell parts and other unwanted substances.
Previous research has found the greatest risk factor for developing Parkinson’s disease and dementia with Lewy bodies (DLB) is carrying a pathogenic variant in the GBA1 gene. These harmful variants reduce the activity of an enzyme called glucocerebrosidase (GCase), which is important for cells’ recycling process in lysosomes. However, it has been unknown why some people who carry pathogenic GBA1 variants develop PD whereas others do not.
To address this, the current study identified Commander complex genes and corresponding proteins that modulate GCase activity specifically in the lysosome. By examining the genomes from two independent cohorts (the UK Biobank and AMP-PD), the scientists found loss-of-function variants in Commander genes in people with PD compared to those without it.
“This suggests that loss-of-function variants in these genes increase Parkinson’s disease risk,” Krainc said.
New drug targets to improve lysosomal function
Lysosomal dysfunction — or when a cell’s recycling system malfunctions — is a common feature of several neurodegenerative diseases, including PD. This study reveals that the Commander complex plays an important role in maintaining lysosomal function, suggesting that drugs that help Commander proteins work better might also improve the cell’s recycling system.
Future research will need to determine the extent to which the Commander complex plays a role in other neurodegenerative disorders that exhibit lysosomal dysfunction.
“If Commander dysfunction is observed in these individuals, drugs that target Commander could hold broader therapeutic potential for treating disorders with lysosomal dysfunction,” Krainc said. “In this context, Commander-targeting drugs could also complement other PD treatments, such as therapies aiming to increase lysosomal GCase activity, as potential combinatorial therapy.”
Other Northwestern authors include first co-authors postdoctoral fellow Georgia Minakaki, PhD, and Nathaniel Safren, PhD, research assistant professor in the Ken and Ruth Davee Department of Neurology, as well as postdoctoral fellow Bernabe I. Bustos, PhD, and Niccolo Mencacci, MD, PhD, assistant professor of Neurology.
Funding for this study was provided by a Research Program Award (R35).
