The Parkinson’s disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons

Abstract

Variants in theCTSBgene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinson’s disease (PD). However, neither the specificCTSBvariants driving these associations nor the functional pathways that link catB to PD pathogenesis have been characterized. CatB activity contributes to lysosomal protein degradation and regulates signaling processes involved in autophagy and lysosome biogenesis. Previousin vitrostudies have found that catB can cleave monomeric and fibrillar alpha-synuclein, a key protein involved in the pathogenesis of PD that accumulates in the brains of PD patients. However, truncated synuclein isoforms generated by catB cleavage have an increased propensity to aggregate. Thus, catB activity could potentially contribute to lysosomal degradation and clearance of pathogenic alpha synuclein from the cell, but also has the potential of enhancing synuclein pathology by generating aggregation-prone truncations. Therefore, the mechanisms linking catB to PD pathophysiology remain to be clarified. Here, we conducted genetic analyses of the association between common and rareCTSBvariants and risk of PD. We then used genetic and pharmacological approaches to manipulate catB expression and function in cell lines and induced pluripotent stem cell-derived dopaminergic neurons and assessed lysosomal activity and the handling of aggregated synuclein fibrils. We find that catB inhibition impairs autophagy, reduces glucocerebrosidase (encoded byGBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction ofCTSBgene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereasCTSBgene activation enhances fibril clearance. In midbrain organoids and dopaminergic neurons treated with alpha-synuclein fibrils, catB inhibition potentiates the formation of inclusions which stain positively for phosphorylated alpha-synuclein. These results indicate that the reduction of catB function negatively impacts lysosomal pathways associated with PD pathogenesis, while conversely catB activation could promote the clearance of pathogenic alpha-synuclein.

Cathepsin-mediated regulation of alpha-synuclein in Parkinson’s disease: a Mendelian randomization study

“…The findings of our study suggest that enhancing CTSB activity could mitigate the progression of PD by promoting the degradation of alpha-synuclein. This observation aligns well with the cellular experiments conducted by Jace Jones-Tabah et al (2023) , which demonstrated that reduced expression of the CTSB gene impairs the degradation of preformed alpha-synuclein fibrils in cell lines. This correlation underscores the potential of CTSB activity modulation as a therapeutic strategy for PD.…”

Exploring the Association between Cathepsin B and Parkinson’s Disease

“…Furthermore, Jones-Tabah and colleagues analyzed genetic data from multiple sources, including the Fox Investigation for New Discovery of Biomarkers (BioFIND), the Harvard Biomarker Study (HBS), the Parkinson's Progression Markers Initiative (PPMI), the Parkinson's Disease Biomarkers Program (PDBP), the International LBD Genomics Consortium (ILBDGC), and the STEADY-PD III Investigators. Their findings were in line with the other studies since they also suggested that rare variations in the CTSB gene might contribute to an increased risk of PD [17]. Sjödin and colleagues conducted a pilot study combining solid-phase extraction and parallel reaction monitoring mass spectrometry and discovered that the concentration of Cathepsin B decreased [34].…”

“…The work by McGlinchey and collaborators implicated Cathepsin B as essential in α-synuclein lysosomal degradation [35,36]. Remarkably, Jones-Tabah and colleagues performed various experiments to demonstrate that Cathepsin B might enhance the clearance of fibrillar alpha-synuclein, increase lysosomal functionality, and boost glucocerebrosidase activity in dopaminergic neurons [17].…”

“…Moreover, Milanowski and collaborators performed a Whole Exome Sequencing (WES) analysis in a PD family, confirming the possible role of the CTSB gene [16]. Jones-Tabah and colleagues used genetic data from the Fox Investigation for New Discovery of Biomarkers (BioFIND), the Harvard Biomarker Study (HBS), the Parkinson's Progression Markers Initiative (PPMI), the Parkinson's Disease Biomarkers Program (PDBP), the International LBD Genomics Consortium (ILBDGC), and STEADY-PD III Investigators, observing that rare variations in the CTSB gene have been associated with an elevated risk of PD [17]. Despite the growing number of evidence, the association between circulating Cathepsin B levels and Parkinson's Disease risk is still uncertain, primarily due to the small sample sizes of the studies, limited follow-up duration, and the potential risk of reverse causality.…”

Cathepsin in Alzheimer's Disease, Parkinson's Disease and Dementia with Lewy Bodies: Mendelian Randomization Study

“…According to new research, decreased cathepsin B function hinders lysosomal pathways linked to PD development, whereas increased cathepsin B activation may enhance the removal of pathogenic α-syn [53]. In cellular models of PD, the protein or activity levels of cathepsin B are decreased [54,55].…”