Objective: To find differential biological processes between synucleinopathies (MSA and PD).

Background: Multiple system atrophy (MSA) is an oligodendroglial sinucleinopathy that is often misdiagnosed as Parkinson’s disease PD (1), especially at early stages. The molecular pathogenesis of the disease is still greatly unknown. Gene Set Enrichment Analysis (GSEA)(2) method for functional analysis of transcriptomic data identifies biological pathways enriched in a differentially expressed gene list to unveil biological processes involved in disease.

Method: We extracted blood from 20 MSA, 10 PD cases and 10 healthy controls from the Catalonian MSA registry. Subjects were gender and age-matched between groups. RNA was isolated using PAXgene Blood RNA Kit (QIAGEN). Genome-wide gene expression analysis was done using the Affymetrix Clariom™D array (Thermo Fisher Sci.). Differential transcript expressions were analyzed with limma(3) method resampling 100 times. A GSEA pre-ranked analysis was performed, using a score based on the sum of expression fold-change among the 100 iterations, with the gene set collection C5 GO biological process from MSigDB, considering only top 100 enrichment score gene sets with p value<0.05.

Results: In PD versus controls, 17% of the overexpressed sets were related to protein regulatory processes, 10% to transcriptional processes, 10% to vesicle/vacuolar transport/formation/organization, and 1% to telomere maintenance (FDR p< 0.01). These GO terms were underrepresented when comparing MSA to PD cases (FDR p <0.001). From the 56 gene sets with significant p value that were unrepresented in PD compared to controls, 26 were related to development/differentiation processes (16 of these specifically related to neurons).  MSA cases, compared to PD showed an overrepresentation of autonomic system processes (7%) including regulation of urine volume and blood pressure, and 6% to neurotransmission (FDR<0.04).

Conclusion: GSEA reveals different biological processes including transcription, protein regulation, vesicle formation and telomere maintenance in blood from PD cases in contrast to gene sets involved with autonomic regulatory processes and neurotransmission in MSA cases. Furthermore, there seems to be downregulation of neuronal cell differentiation and development.

References: 1. Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, et al. When DLB, PD, and PSP masquerade as MSA. Neurology. 2015 Aug 4;85(5):404–12. 2. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci. 2005 Oct 25;102(43):15545–50. 3. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res [Internet]. 2015 Apr 20;43(7):e47.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unraveling-biological-processes-implicated-in-msa-and-pd-by-transcriptomic-analysis/