Gene Co-Expression Network Analysis Implicates microRNA Processing in Parkinson’s Disease Pathogenesis

Abstract

Background: Recent advances in genetics have provided insights into important inherited causes of Parkinson’s disease (PD), but the underlying biological mechanisms are still incompletely understood. Gene expression studies have pointed toward the dysregulation of neuroinflammation, mitochondrial function, and protein degradation pathways. Objective: We aimed to identify groups of dysregulated genes in PD. Methods: In order to increase statistical power and control for potential confounders, we re-analyzed transcriptomic data from PD patients and model systems, integrating additional genomic data using a systems biology approach. Using weighted gene co-expression network analysis, we partitioned genes into co-expressed modules. Results: One co-expression module, M13, had an expression trajectory that was highly correlated with PD, was not characterized by any specific cell type markers, and was enriched in PD genes identified by genome-wide association studies. Genes within M13 seemed to be related to global microRNA biogenesis, and DICER1 and AGO3 were highly connected within the module. The NUCKS1 gene, previously identified as part of the PARK16 locus, was also a hub gene within M13. Conclusion: These results suggest that microRNA processing and function may play a role in the pathogenesis of PD, and thus may represent a useful target for future drug development.

Functional association between NUCKS1 gene and Parkinson disease: A potential susceptibility biomarker

“…The casein kinase 2 has been reported to be involved in altering the dopamine signaling as well as hyper phosphorylation of alpha-synuclein [30,31] and cyclin-dependent kinases, suppress dopamine D1 signaling in the striatum by phosphorylation of postsynaptic protein DARPP-32 [32]. Some previous studies have also reported that cell-cycle protein mediates the degeneration of dopaminergic neurons [7,33]. An earlier study reported that rs823128 variant of NUCKS1 might affect PD risk by altering the transcription factor-binding capability of the genes [34] and also reported as hub gene in a gene network analysis study on Parkinson's disease [35].…”

The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

“…α-Syn also regulates protein ubiquitination, chaperone activity, kinase-dependent pathways, and, lastly, the metabolism of dopamine [67][68][69][70]. Indeed, genome-wide association studies (GWAS) identified that α-Syn expression, glycosphingolipid biosynthesis, and the protein ubiquitination are pathways affected by single nucleotide polymorphisms (SNP) and a set of microRNAs differentially expressed in PD [71][72][73].…”

Noncoding RNAs and Midbrain DA Neurons: Novel Molecular Mechanisms and Therapeutic Targets in Health and Disease

“…In addition, the consequent downregulation of SNCA due to miR-7 and miR-153 protects cells from oxidative stress [ 34 , 35 ]. A further GWAS also revealed that SNCA expression is affected by a set of miRNAs differentially expressed in PD, such as miR-34b/c and miR-214 , which directly bind its 3′ UTR [ 36 ]. As abovementioned, miRNAs represent promising biomarkers for early recognition of the onset of disease and possible therapeutic targets.…”