Table 4.

Target simulation for significantly dysregulated miRNAs in Parkinson's disease versus controls using Boolean modelling applied in the Parkinson’s disease map

Pathway category	Dysregulated molecules	Simulated elements	Simulated behaviour	Interpretation
TFEB activity	MITF, PTEN, WDR45, RAB7A, PRKAG2, BECN1, ATP6VOD1, ATP6V1H, ATP6V1E1, ATP6V0E1, ATP6V1C1	Lysosomal acidification; autophagy	Impaired acidification; compromised autophagy	Alterations in TFEB activity affect autophagy and lysosomal function, crucial for the degradation of α-Syn aggregates in Parkinson’s disease.
ER stress signalling	CEBPB, DDIT4, MAP1LC3B, BECN1, HSP90B1	Autophagy; unfolded protein response (UPR); chaperone activity	Impaired autophagy; activated UPR; modified chaperone activity	Chronic ER stress and the unfolded protein response contribute to the pathogenesis of Parkinson’s disease by affecting protein folding and clearance mechanisms
Calcium signalling	ATP1A1, ATP1B1, SLC8A2, CACNA1D, CACNA2D2, CACNA2D3, CACNB2, ERN2, EIF2AK2, CAMK2, CAMK2B, PPP3CA, PPP3CB, YWHAB, RPS6KA1, RPS6KA3	Calcium homeostasis; CREB signalling	Disrupted calcium homeostasis; altered CREB signalling	Dysregulation of calcium signalling can lead to neuronal excitotoxicity and affect various signalling pathways implicated in Parkinson’s disease
Dopaminergic transcription	NR4A2, NCOR2, FOXA2, SNCA, PARK7(DJ1), CGH1, TH, DDC, SLC18A, ALC6A3, CFLAR, SOD1, COX5B, COX6A1, NDUFB8, BDNF, RET, ALDH1A1, FOXO1, FOXO3, KLC1, MAP1B, EN1, FOXA1, FOXA2	Transcriptional regulation; mitochondrial function	Dysregulated transcription; compromised mitochondrial function	Impairment in the transcriptional machinery and mitochondrial dysfunction are key features in the loss of dopaminergic neurons in Parkinson’s disease.
PPARGC1A activity	SIRT1, ESR, IDH3B, IDH3G, COX5B, COX6A, COX6B1, COX7A2, COX7C, SDHB, TOMM20, SURF1, VDAC1, TFB2M	Mitochondrial biogenesis; respiratory function	Altered mitochondrial biogenesis; impaired respiratory function	PPARGC1A is a key regulator of mitochondrial biogenesis and function, and its dysregulation is implicated in the mitochondrial dysfunction observed in Parkinson’s disease.

The 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 are simulated or affected due to the molecular dysregulation. Column ‘simulated behaviour’ describes the consequent aberrant behaviour or states induced by the pathway dysregulation(s).