Objective: Sequence RNA in cortical samples taken from living PD patients to detect significant differentially expressed genes (DEGs) and altered biological pathways when compared to controls.

Background: The development of next-generation sequencing platforms has made sequencing the transcriptome feasible at a fraction of the time and cost. For Parkinson’s disease (PD), this opens the possibility of capturing ongoing neurodegenerative processes at the transcriptional level. To date, examinations of the PD transcriptome have mostly been limited to non-CNS or cadaveric sources of tissue, which is likely at best a proxy of the disease process in the living brain. Small volume brain biopsies that can be safely obtained during deep-brain stimulation surgery for PD offer a feasible and novel alternative to these more traditional biological specimens (Xu et al., 2013).

Methods: Total RNA was extracted from cortical biopsies in 6 patients with PD and 6 controls, then sequenced on the Illumina HiSeq 2500 platform using a stranded paired-end protocol. This yielded approximately 90 million reads per sample, which we analyzed for differential expression using edgeR (v.3.8.6). Pathway enrichment and induced network analyses were also performed using the freely available analysis tools from the Gene Ontology Consortium and ConsensusPathDB.

Results: At a false discovery rate of <0.05, 763 DEGs were identified. Pathway analysis showed enrichment of genes responsible for regulating inflammatory response processes, tumor necrosis factor production and cellular response, the innate immune response and negative regulation of apoptotic processes. Disease relevant genes involved in these biological processes include CD44, Interleukin-10, GDNF, IL1β, and NF-kappa-B inhibitor alpha. Interestingly, induced network analysis revealed a robust network surrounding the NF-κB complex.

Conclusions: To our knowledge this is the first demonstration of differential CNS gene expression and enriched gene ontologies in cortical samples from living PD patients. The detected alterations offer a wealth of data that could facilitate identification of genetic biomarkers for diagnosis and treatment of PD. Significant results from pathway analysis and induced networks point to dysregulation of processes surrounding the NF-κB complex, lending further evidence to the growing body of literature relating neuroinflammation to PD and other neurodegenerative diseases.

References: Xu H, Belkacemi L, Jog M, Parrent A, Hebb MO. Neurotrophic factor expression in expandable cell populations from brain samples in living patients with Parkinson’s disease. FASEB J. 2013;27(10):4157-4168. doi:10.1096/fj.12-226555.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evidence-for-dysregulation-of-inflammatory-mechanisms-involving-the-nf-%ce%bab-complex-in-the-living-parkinsonian-brain/