A long -term mystery in the investigation of Parkinson’s disease is why some individuals wear pathogenic variants that increase their risk of PD, develop the disease, while others who also wear such variants do not. The prevailing theory has suggested that additional genetic factors can play a role.
To answer this question, a new study from Northwestern Medicine used modern technology, called CRISPR interference, to systematically investigate every gene in the human genome. The scientists identified a new series of genes that contribute to the risk of Parkinson’s disease, which opens the door to previously untouched goals for treating PD.
More than 10 million people worldwide live with PD, the second most common neurodegenerative disease after Alzheimer’s disease.
The study was published on 10 April in the magazine Science.
Our study shows that a combination of genetic factors plays a role in the manifestation of diseases such as Parkinson’s disease, which means that therapeutic targeting of various important routes must be considered for such disorders. “
Dr. Dimitri Krinc, corresponding author, chairman of Davee Department of Neurology and director of the Feinberg Neuroscience Institute at the Northwestern University Feinberg School of Medicine
“It is also possible to identify such genetic factors in sensitive individuals by studying tens of thousands of patients, which is challenging and expensive,” Krinc said. “Instead, we used a genome-wide CRISPR interference screen to silence each of the protein-coding human genes in cells and that importantly identified 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 non -recognized role in supplying specific proteins to the lysosome, part of the cell that works as a recycling center, which breaks down waste materials, old cell components and other unwanted substances.
Previous research has found the largest risk factor for developing Parkinson’s disease and dementia with Lewy Bodies (DLB) is a pathogenic variant in the GBA1 gene. These harmful variants reduce the activity of an enzyme called GlucocerebroSidase (GCAS), which is important for the recycling process of cells in lysosomes. However, it is unknown why some people who wear pathogenic GBA1 variants develop PD, while others don’t. To tackle this, the current study commander identified complex genes and corresponding proteins that modulate gas sase in the lysosome. By investigating two independent cohorts (the British Biobank and AMP-PD), the scientists found variants of functions of function in commander genes in people with PD compared to those without.
“This suggests that variants of loss of function in these genes increase the risk of Parkinson’s health insurance,” said Krinc.
New goals from the drug to improve the lysosomal function
Lysosomal dysfunction – or when the recycling system of a cell Storte – is a common characteristic of various neurodegenerative diseases, including PD. This study shows that the commander complex plays an important role in maintaining the lysosomal function, which suggests that medicines that help commander -proteins work better, including the recycling system of the cell.
Future research will have to determine to what extent the commander complex plays a role in other neurodegenerative disorders that show lysosomal dysfunction.
“If commander’s function is observed in these persons, drugs that focus on commander can have a broader therapeutic potential for the treatment of disorders with lysosomal dysfunction,” said Krobinc. “In this context, drugs for commanders can also provide a supplement to other PD treatments, such as therapies aimed at increasing lysosomal gcase activity, as a potential combination therapy.”
Other northwestern authors are first co-authors postdoctoral guy Georgia Minakaki and research assistant professor of Neurology Nathaniel Safren, as well as postdoctoral guy Bernabe I. Bustos, and assistant professor in neurology Dr. ir. Niccolo Mercacci.
Financing for this study was provided by Research Program Award (R35).
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Journal Reference:
Minakaki, G., et al .. (2025). Commander Complex regulates the lysosomal function and is involved in the risk of Parkinson’s health insurance. Science. doi.org/10.1126/science.adq6650.