Pietrantonio, I. | bioRxiv Science

bioRxiv2026

Neuronal secretome from bipolar patient-derived neurons alters network function and contains candidate biomarkers for diagnosis and lithium response

Delayed diagnosis and treatment are a major burden to patients with bipolar disorder. While lithium is the most effective treatment against mania, depressive episodes, and suicide, only 30% of patients respond to it fully. Currently there are no reliable methods to predict lithium responsiveness. To address these challenges, we aimed to identify potential diagnostic and treatment response biomarkers for BD, in addition furthering understanding of BD pathophysiology. Here, we leveraged human induced pluripotent stem cell (hiPSC) derived neurons from lithium responsive (LR), lithium non-responsive (LNR), and healthy age-matched controls (CTL). We found extracellular vesicle (EV) cargos from hiPSC-derived neurons are indicative of disease state and treatment-response. Unbiased proteomic and miRNA profiling identified 10 proteins and 13 miRNAs that were differentially expressed in BD EVs relative to CTL, as well as distinct molecular signatures separating LR ad LNR groups. These differences converged on pathways related to synaptic function, neurotrophic signalling, and cellular stress responses. Additionally, we found the BD neuronal secretome alters activity in non-BD neuronal networks. Chronic treatment of CTL cultures with BD neuron-conditioned media modified the proportion of active neurons and the frequency and amplitude of calcium transients in individual neurons. We demonstrate that neuronal EVs contain molecular signatures of disease state and treatment response in BD and identify the BD secretome as an active regulator of neuronal network homeostasis. This study provides novel insights into the pathophysiology of BD and candidate biomarkers for personalized BD diagnosis and treatment selection.

neuroscience↗

bioRxiv2023

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

Variants in the CTSB gene encoding the lysosomal hydrolase cathepsin B (catB) are associated with increased risk of Parkinsons disease (PD). However, neither the specific CTSB variants 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. Previous in vitro studies 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 rare CTSB variants 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 by GBA1) activity, and leads to an accumulation of lysosomal content. In cell lines, reduction of CTSB gene expression impairs the degradation of pre-formed alpha-synuclein fibrils, whereas CTSB gene 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.

neuroscience↗