Objective: To identify novel gene regulatory events associated with Parkinson’s disease with dementia (PD-D).

Background: PD-D is associated with the spread of degenerative pathology to vulnerable cortical regions, including the posterior cingulate cortex. RNA sequencing (RNA-seq) is an attractive approach to uncovering the etiology of this and other complex neurodegenerative diseases.

Methods: We used RNA-seq to characterize gene and isoform expression within the posterior cingulate cortex of healthy controls (n=11), Parkinson’s disease subjects (n=13) without dementia (PD), and PD-D subjects (n=10). We confirmed differential expression and alternative splice variant expression of numerous transcripts using qRT-PCR.

Results: Compared to controls, genes overexpressed in both PD and PD-D states were involved with an immune response, while genes under-expressed in both PD and PD-D were involved in signal transduction as well as components of the cytoskeleton. Alternative splicing analysis produced a pattern of immune and RNA processing disturbances, often associated with predicted structural differences in the encoded proteins between PD and PD-D. Importantly, genes with the greatest degree of differential expression did not overlap with genes exhibiting significant alternative splicing activity.

Conclusions: PD and PD-D patients share cortical expression changes to immune response and neurotransmitter signaling. These changes precede overt neuronal synuclein pathology. In addition, disease associated alternative splicing changes often do not result in overall changes to the expression of affected genes, but can affect the expression of key functional domains of the encoded proteins. Moreover, there is significant dysregulated splicing in the cortices of patients with both PD and PD-D.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/next-generation-profiling-to-identify-the-molecular-etiology-of-parkinsons-disease-dementia/