CRISPR Pinpoints New Key Genes Driving Parkinson's Disease

Researchers identify novel genes and a cellular pathway associated with Parkinson’s disease (PD) risk, uncovered through a genome-wide CRISPR interference screen (1^✔ ✔Trusted Source
Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk

Go to source). More than 10 million people worldwide are living with PD, the second-most common neurodegenerative disease after Alzheimer's disease.

The study was published 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.”

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.

Commander Complex Genes Linked to Parkinson's Risk in GBA1 Variant Carriers

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.

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“This suggests that loss-of-function variants in these genes increase Parkinson’s disease risk,” Krainc said.

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.”

Reference:

1. Commander complex regulates lysosomal function and is implicated in Parkinson’s disease risk - (https://www.science.org/doi/10.1126/science.adq6650)

Source-Eurekalert