# RNA networks of lysosomal-related biomarkers in Parkinson’s disease and their correlations with freezing of gait-associated genes

## TL;DR

This study identifies FGD4 and MAN2B1 as lysosomal biomarkers for Parkinson’s disease, linked to freezing of gait and inflammation.

## Contribution

The novel contribution is the identification of FGD4 and MAN2B1 as PD biomarkers with strong correlations to freezing of gait and lysosomal function.

## Key findings

- FGD4 and MAN2B1 were identified as key lysosomal biomarkers for Parkinson’s disease.
- These biomarkers are strongly correlated with freezing of gait-related genes and inflammation markers.
- qPCR validation confirmed higher expression of FGD4 and MAN2B1 in PD patients compared to controls.

## Abstract

Parkinson’s disease (PD) is influenced by various factors, with lysosome function playing a critical role. However, the specific involvement of lysosome-related genes (LRGs) in PD remains unclear.

This study aims to identify biomarkers specific to PD that exhibit robust disease prediction capabilities.

Datasets for patients with PD, LRGs, and inflammation-related genes (IRGs) were retrieved from online databases. miRNAs and mRNAs within key modules were selected through Weighted Gene Co-expression Network Analysis (WGCNA), revealing strong associations with PD. A miRNA-mRNA network was constructed based on highly correlated PD-related LRGs (PD-LRGs) and miRNAs within these modules. Candidate genes were identified by intersecting target genes, differentially expressed genes (DEGs), PD-LRGs, and module-associated mRNAs. Machine learning and expression validation were employed to confirm these biomarkers. A nomogram was established, and its diagnostic performance was evaluated using a confusion matrix. Drug predictions were conducted based on these biomarkers. Spearman’s correlation analyses were performed to assess the relationship between IRGs, freezing of gait (FOG)-related genes, and biomarkers. Molecular regulatory networks were constructed using datasets and online resources. Finally, clinical samples were collected for quantitative PCR (qPCR) validation of biomarker expression.

Key modules related to PD were identified, comprising 190 miRNAs and 7,633 mRNAs. A miRNA-mRNA network was constructed based on 55 PD-LRGs and 181 miRNAs, resulting in the identification of 26 candidate genes strongly linked to lysosomal function. FGD4 and MAN2B1 were selected as biomarkers, and a gene expression-based risk prediction table was created. These biomarkers were significantly correlated with IRGs and several FOG-related genes. Gene localization analysis revealed that FGD4 and LRRK2, both critical to the FOG pathway, are located on chromosome 12. Drug prediction revealed that Tetrachlorodibenzodioxin and bisphenol A target both FGD4 and MAN2B1. qPCR analysis confirmed that FGD4 and MAN2B1 expression levels were significantly higher in patients with PD compared to healthy controls (p < 0.05).

FGD4 and MAN2B1 act as lysosomal biomarkers associated with PD and exhibit strong correlations with genes involved in PD-related freezing of gait. This study offers novel insights into PD diagnosis.