Summary: Researchers have long wondered why some people with high-risk Parkinson’s gene variants develop the disease while others don’t. A new study has uncovered that additional genetic players, particularly the Commander gene complex, influence whether the disease manifests.
Using CRISPR interference to screen the entire genome, scientists identified how Commander proteins impact lysosomal function — a key cellular recycling system tied to Parkinson’s pathology. These findings not only clarify disease mechanisms but also introduce new targets for potential therapies.
Key Facts:
- Commander Genes Identified: A set of 16 Commander proteins helps regulate lysosomal function, influencing Parkinson’s disease development.
- CRISPR-Based Screening: Genome-wide CRISPR interference revealed which genes modulate GCase activity and Parkinson’s risk.
- New Drug Pathways: Enhancing Commander protein function may offer a therapeutic route to restore lysosomal health and slow neurodegeneration.
Source: Northwestern University
A longstanding mystery in Parkinson’s disease 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 study from Northwestern Medicine 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 Parkinson’s disease, 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.
The study was published April 10 in the journal Science.
“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 Dr. Dimitri Krainc, chair of Davee department of neurology and director of the Feinberg Neuroscience Institute at Northwestern University Feinberg School of Medicine.
“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 and research assistant professor of neurology Nathaniel Safren, as well as postdoctoral fellow Bernabe I. Bustos, and assistant professor of neurology Dr. Niccolo Mencacci.
Funding: Funding for this study was provided by Research Program Award (R35).
About this genetics and Parkinson’s disease research news
Author: Kristin Samuelson
Source: Northwestern University
Contact: Kristin Samuelson – Northwestern University
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk” by Dimitri Krainc et al. Science
Abstract
Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk
Variants in GBA1 resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of GBA1 variants suggests that additional genes contribute to PD and DLB manifestation.
By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain–containing 3 (COMMD3) protein, a component of the COMMD/coiled-coil domain–containing protein 22 (CCDC22)/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity.
Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk.
Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.
