Transcriptome Analysis Reveals a Two-Gene Signature Links to Motor Progression and Alterations of Immune Cells in Parkinson’s Disease

Abstract

Background: The motor impairment in Parkinson’s disease (PD) can be managed but effective treatments for stopping or slowing the disease process are lacking. The advent of transcriptomics studies in PD shed light on the development of promising measures to predict disease progression and discover novel therapeutic strategies. Objective: To reveal the potential role of transcripts in the motor impairment progression of patients with PD via transcriptome analysis. Methods: We separately analyzed the differentially expressed genes (DEGs) between PD cases and healthy controls in two cohorts using whole blood bulk transcriptome data. Based on the intersection of DEGs, we established a prognostic signature by regularized regression and Cox proportional hazards analysis. We further performed immune cell analysis and single-cell RNA sequencing analysis to study the biological features of this signature. Results: We identified a two-gene-based prognostic signature that links to PD motor progression and the two-gene signature-derived risk score was associated with several types of immune cells in blood. Notably, the fraction of neutrophils increased 5% and CD4+ T cells decreased 7% in patients with high-risk scores compared to that in patients with low-risk scores, suggesting these two types of immune cells might play key roles in the prognosis of PD. We also observed the downregulated genes in PD patients with high-risk scores that enriched in PD-associated pathways from iPSC-derived dopaminergic neurons single-cell RNA sequencing analysis. Conclusion: We identified a two-gene signature linked to the motor progression in PD, which provides new insights into the motor prognosis of PD.

The role of ADAR editing and nonsense-mediated decay in Parkinson’s Disease

“…Li et al [122], observed 17 A-t o-I editing sites in NCOR1, BST1, and KANSL1 genes with potential risk associations for PD in a study of 380 PD and 178 healthy controls samples from PPMI. Additionally, alterations in ADAR editing at 57 sites correlated with the progression of cognitive symptoms in PD patients [122].…”

“…ADAR2 and 3 expression was also highest in either prodromal or PD samples depending on whether sexes are combined. Other studies have observed decreased editing frequency [121] and significant differences in ADAR expression [122] in PPMI PD blood; however, these studies did not compare PD males to PD females or PD to prodromal in their analyses and included samples regardless of age; whereas, we chose samples from individuals 65 years or older.…”

“…RNA editing by Adenosine Deaminases Acting on RNA (ADARs), which causes adenosine to inosine deamination, is the most common mechanism of post-transcriptional RNA editing in the nervous system and is integral to neurodevelopment and response to infection/inflammation [15][16][17][18]. PD is a complex disease with heterogenous phenotypes that vary across individuals, as well as by age and sex [19][20][21], therefore, it is likely that multiple interacting factors, such as the aging process [22,23] and hormones [24][25][26], in addition to genetic [11][12][13][14]27] and other confounding factors, including dynamic ADAR editing [14,28,29], may play a role in PD pathology.…”

“…The genes associated with the edits were enriched in neurodegeneration-related functions, with a subset of edits determined to change miRNA binding sites [52]. Additionally, a recent study of A to I editing in the transcriptomes of 380 PD patients and 178 Healthy Controls identified 17 ADAR edited sites that could contribute to increased genetic risk of PD through RNA editing [34]. While the 17 sites were associated with NCOR, KANSL, and BST genes in the Li et al [34] study (2023), 57 additional sites were correlated with the progression of cognitive symptoms in PD cases [34].…”

“…In a study examining post-mortem brain tissue for editing in microRNA (miRNA), Lu et al[33], identified a number of miRNA editing sites that were edited at significantly different editing levels between PD and healthy controls (2022). Li et al (2024) observed multiple ADAR editing sites that could be integral to PD physiology in a recent study of PD blood samples[34]. These findings suggest that changes in ADAR editing patterns may play an impactful role in the pathology of PD affecting various tissue types.…”