Transcriptomic Analysis and Multiple Machine Learning Approaches Identify ZDHHC20 and Its Highly Correlated Gene AK5 as Biomarkers in Multiple System Atrophy.

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder lacking effective diagnostic tools. While protein palmitoylation is crucial for neuronal function, its specific role in MSA pathogenesis remains unexplored. We integrated bulk and single-nucleus RNA sequencing (snRNA-seq) data from postmortem MSA brain tissues. Eight machine learning algorithms were utilized to screen palmitoylation-related genes. Downstream analyses, including functional enrichment, cellular deconvolution, and pseudotime trajectory inference, were then conducted. ZDHHC20 and its highly correlated gene, AK5, were identified as hub genes. Both demonstrated significant downregulation in MSA, particularly within the cerebellar white matter. Functional enrichment analysis linked this expression pattern to mitochondrial dysfunction and impaired energy metabolism. Furthermore, snRNA-seq revealed that ZDHHC20 and AK5 are predominantly expressed in oligodendrocytes and exhibit lower expression levels along the developmental trajectory in MSA compared to healthy controls. ZDHHC20 and AK5 represent promising biomarkers for MSA. These findings provide new insights into the diagnosis and treatment of MSA.