Table 5.
Target simulation for significantly dysregulated miRNAs in progressive supranuclear palsy versus controls using Boolean modelling applied in the Parkinson's disease map
| Pathway category | Dysregulated molecules | Simulated elements | Simulated behaviour | Interpretation |
|---|---|---|---|---|
| TFEB activity | ARP6V0B, CLN3, GLA | Lysosomal acidification; lysosomal membrane organization | Reduced acidification; disrupted membrane organization | Disruption in TFEB-mediated autophagy and lysosomal biogenesis impairs cellular waste management, contributing to mitochondrial dysfunction |
| ER stress signalling | SIGMAR1, ATG7, EIF2AK3 | Autophagy; ERAD; SIGMAR1 | Reduced autophagy; enhanced ERAD; stable SIGMAR1 activity; EIF2AK3 | ER stress alters cellular survival and apoptotic pathways. Dysregulation in autophagy and ERAD may contribute to neuronal death in progressive supranuclear palsy |
| Calcium signalling | CAMK2G, RPS6KA3, NCS1 | CREB1; TORC1 and TORC2; NR4A2; PPARGC1; dopamine receptor endocytic activity | Inhibited CREB1; inhibited TORC1/2; downregulated NR4A2; downregulated PPARGC; reduced dopamine receptor endocytic activity | Calcium signalling dysregulation disrupts neuronal transcriptional responses, exacerbating progressive supranuclear palsy's neurodegenerative process |
| Dopaminergic transcription | COX8A | Mitochondrial biogenesis | Dysregulated biogenesis | COX8A dysfunction underpins compromised mitochondrial health, critical for maintaining dopaminergic neuron integrity in progressive supranuclear palsy |
| PPARGC1 activity | SURF1, COX8A | Mitochondrial transport | Accelerated mitochondrial transport | SURF1 overexpression, likely compensatory, affects mitochondrial dynamics, essential for preserving neuronal health amidst progressive supranuclear palsy pathology |
Pathway categories (n = 5) overlapping between Parkinson’s disease versus controls and progressive supranuclear palsy versus control are shown. Column ‘dysregulated molecules’ refers to the target molecules within the dysregulated pathway(s) in the simulation. Column ‘simulated elements’ reflects on the broader impact at the cellular or system level highlighting the elements that were simulated or affected due to the molecular dysregulation. Column ‘simulated behaviour’ describes the simulation of the consequent aberrant behaviour or states induced by the pathway dysregulation(s).