New Molecular Drivers of Parkinson Disease Discovered, Indicating Potential Treatment Innovations

Researchers discovered new molecular drivers of Parkinson disease (PD) and determined their impact on the functions of genes involved in PD, potentially leading to novel treatments, according to study findings published today in Nature Communications.

PD risk has remained largely unknown, as nearly 80% of cases have no attributable cause. While the other 20% of PD cases are linked to genetic variants, the biological impact of these genes is unclear.

As the study authors note, gene network analysis has been shown to provide an unbiased approach to identify gene coexpression/coregulation patterns in higher organisms for discovery of novel pathways and gene targets in various biological processes and complex human diseases. In previous studies, researchers have utilized these analyses to form a multiscale network model of Alzheimer disease (AD), which validated several predicted key regulators of AD. This approach has yet to be used toward PD, however, due to the lack of molecular profiling data from a large number of postmortem brain samples.

Using the ensemble of all the existing human brain gene expression data sets in PD, researchers from Mount Sinai developed a multiscale gene network analysis (MGNA) model followed by a comprehensive functional validation to distinguish top key regulators:

• Researchers combined data from 8 different studies that included postmortem analyses of the substantia nigra, the part of the brain most affected by PD
• 83 postmortem brain samples from patients with PD were compared with 70 controls without PD

After applying MGNA to the combined data set, researchers identified 946 differentially expressed genes (DEGs) that had never been previously linked to PD. After delineating which DEGs were downregulated, linked to enriched synaptic function and metabolism-related gene ontology analysis terms, and upregulated, associated with spinal cord development and embryonic digit morphogenesis, researchers analyzed genes through a network-based enrichment analysis for synaptic transmission and dopamine metabolism, which are the top disrupted pathways in PD.

The analysis revealed that 21 of the 32 top-ranked downregulated genes and 2 of the 11 top-ranked upregulated genes were present in the meta-analysis with consistent regulation. The STMN2 gene, which the analysis identified as a key regulator of the PD molecular network, was shown to be a chief influence on the associated genes.

Limitations to the study, however, include the small sample size for the multiscale network analysis. To validate findings among PD communities, further analysis on larger study cohorts is warranted, but contributor Zhenyu Yue, MD, professor of neurology and neuroscience at the Icahn School of Medicine and the director of Basic and Translational Research in Movement Disorders, noted that regardless of the limitations, published research opens up a new avenue for studying the disease.

“The new genes we identified suggest that new pathways should be considered as potential targets for drug development, particularly for idiopathic Parkinson cases,” said Yue.

Reference

Wang Q, Zhang Y, Wang M, et al. The landscape of multiscale transcriptomic networks and key regulators in Parkinson’s disease [published online November 20, 2019]. Nat Commun. doi: 10.1038/s41467-019-13144-y.