Biology subjects

Deyab, G.

Publications and source records attributed to Deyab, G..

3 recordsLinked to original sources

bioRxiv2026

Integration of iPSC-derived microglia into human midbrain organoids enhances microglial maturation and inflammatory signaling

Microglia are the resident immune cells of the central nervous system and play key roles in the healthy brain during development and adulthood, as well as during neurodegenerative diseases - including Parkinsons disease (PD). Yet the role of microglia in PD pathogenesis has not been fully elucidated. Limitations of 2D cell culture and animal models in simulating human microglia in the brain parenchyma have contributed to this knowledge gap. Human midbrain organoids (hMOs) provide a promising model that can recapitulate elements of PD pathology but lack microglial cells. Here we adapt protocols for the differentiation of hMOs and human iPSC-derived microglia (iMG) to generate iMG-hMO assembloids. Within assembloids, integrated iMG (intMG) express canonical microglia markers and induce the release of cytokines and chemokines. Transcriptomic profiling by single cell RNA sequencing reveals that intMG adopt a more mature and inflammation-responsive state compared to 2D iMG. The integration of microglia results in increased signaling through inflammatory and trophic pathways that drive altered transcriptional signatures of dopaminergic neurons and astrocytes within assembloids. Overall, iMG-hMO assembloids have the potential to more faithfully model the role of microglia and neuroinflammation in PD pathogenesis.

neuroscience↗

bioRxiv2025

Midbrain organoids with an SNCA gene triplication display dopamine-dependent alterations in network activity

Human midbrain organoids (hMOs) show promise as a patient-derived model for the study of Parkinsons disease (PD). Yet, much remains unknown about how accurately hMOs recapitulate key features of PD in the human brain. In both PD patients and animal models, disease progression leads to characteristic changes in neural activity throughout the basal ganglia. Here we demonstrate that patient-derived induced pluripotent stem cell (iPSC) hMOs harboring a triplication in the SNCA gene, encoding -synuclein, a key protein in PD pathogenesis, can recapitulate PD-associated changes in neural activity. Namely, we observe hyperactive network activity in SNCA triplication hMOs, but not in isogenic, CRISPR-corrected iPSC hMOs. These changes are characterized by an increase in the number of bursts and network-wide bursts. Moreover, SNCA triplication hMOs exhibit an increase in network synchrony and burst/network burst strength similar to observations in animal and human PD brains. Subsequently, we show that the observed changes in neuronal activity are attributed to dopamine D2 receptor hypoactivity due to dopamine depletion, which could be reversed by the D2 receptor agonist quinpirole. Thus, hMOs faithfully model network wide electrophysiological changes associated with PD progression and serve as a promising tool for PD research and personalized medicine.

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↗