New research into the link between the CTSB gene and Parkinson's

Summary statement

Researchers analyzed differences between variants in the CTSB gene, which is associated with cell function and plays a potential role in a variety of conditions and pathologies, including in Parkinson’s. They also tested how alternatively reducing or enhancing the function of CatB, the main protein associated with the CTSB gene, could impact alpha-synuclein accumulation in the brain. This has implications for future treatment developments and in better understanding the underlying biological processes influencing Parkinson’s. 

Article review 

Genome-wide association studies (called GWAS) are used by researchers to determine which genes are associated with different biological processes and disease progressions. Regarding Parkinson’s specifically, studies have identified genes like GBA1, SNCA, PINK1, LRRK2, and others that can play different roles in how the condition develops and progresses. Recent studies have identified associations between CTSB and Parkinson’s as well. CTSB is a gene that encodes CatB, a protein involved in the proper functioning of cell lysosomes and the accumulation of alpha-synuclein. The interrelation between lysosomal functioning and alpha-synuclein, and the mediation of both by CTSB and CatB, is complex, but essentially involves CatB not being able to properly help brain cells remove harmful substances before they’re able to build up and cause more damage. 

The authors in this study, published in Molecular Neurodegeneration in 2024, performed comprehensive analyses to determine how variants in the CTSB gene and the expression of the CatB protein can influence Parkinson’s, and which underlying biological mechanisms are most relevant. First, they used a GWAS analysis to help determine which common and rare variants in the CTSB gene were most strongly implicated in Parkinson’s development. They then produced testable lines of cells (lab-derived dopaminergic neurons and other neural cells, called iPSCs) with different levels of the CatB protein being expressed via manipulating CTSB and SNCA – another gene associated with CatB – within these cell lines. By then introducing alpha-synuclein through these cells in a way that simulates how this same process would occur in Parkinson’s, they were able to determine how this process might be impacted by the associated genetic variations they’ve induced in these cell lines.

Once the study had been completed, the researchers did determine that certain CTSB variants are significantly associated with Parkinson’s, and that the strength of that association is different depending on the variant. Most importantly, though, the study findings suggest that reducing the expression of the CatB protein may hinder the ability of lysosomes to help clear harmful alpha-synuclein aggregates from neurons, while conversely enhancing the expression of CatB has the opposite effect and can help promote the removal of harmful alpha-synuclein. 

Essentially, CatB appears to play a role in supporting lysosomes and cell health, and so when it is inhibited or not being naturally produced to a sufficient degree, these findings suggest that it can contribute to a buildup of harmful alpha-synuclein clusters that are one of the key pathological hallmarks of Parkinson’s. 

This study offers important insights into a relatively understudied gene in terms of Parkinson’s development, and a look into the underlying biology that influences that relationship. Identifying new pathways and genes in Parkinson’s provides new opportunities for future research and the potential for the development of disease-modifying therapies with novel targets on different biological mechanisms. 

Instead of a treatment that can just help address your symptoms and help you with your daily functioning but that doesn’t actually prevent the condition from progressing, disease-modifying therapy refers to something that is able to help correct or influence the biological processes that are causing the condition in the first place. If we are able to one day develop targeted therapeutics that work on a single protein that’s associated with someone’s unique genetic signature, it could help stop or slow down the mechanisms of the condition itself. Studies like this are necessary for any of that work to be done. 

While the study authors did not mention specific additional research they would be performing following this work, this study does have clear implications in both exploring the development of potential treatments and disease-modifying therapies, and in overall better understanding the underlying biology of Parkinson’s. They summarize it well in the paper: “Together this evidence highlights CTSB as an important player in the etiology of synucleinopathies such as Parkinson’s disease, and further study of its biology may help to uncover novel therapeutic approaches to this disease” (Jones-Tabah et al., 2024, p. 18). 

Two of the study authors, Dr. Jones-Tabah and Dr. Senkevich, are both supported in part by grants from Parkinson Canada, and we’re proud to highlight the work coming out of Canadian institutes that helps improve our collective understanding of Parkinson’s and that contributes to the future of treatment development. You can read the full research article published in Molecular Neurodegeneration here.