Abstract Details

Consequent to the loss of dopaminergic neurons in the substantia nigra in PD, the dopamine-dependent striatum undergoes molecular changes, resulting in motor  and non-motor symptoms. We sought to understand the molecular mechanisms involved in disease manifestation by investigating transcriptome changes in the PD striatum.

To investigate messenger RNA expression patterns and their regulation by alternative splicing in the striatum in Parkinson’s disease(PD) and Parkinson’s disease dementia(PDD).

We performed RNA-sequencing on post-mortem striatum (caudate and putamen) collected from healthy controls (n=40) and PD (n=35). We additionally compared RNA expression between PDD (n=16) and PD without dementia(n=11). Analysis was performed using Limma (differential gene expression),  Gene set enrichment analysis (pathway enrichment), and Multivariate Analysis of Transcript Splicing(alternative splicing). Significant change in  expression of genes was defined with the log₂ fold change ≥ 0.5 and q-value < 0.05. Significantly spliced events were defined as difference in absolute percent spliced in (PSI) of >10% and q-value <0.05.

Differential gene expression analysis revealed 2405 and 2032 up and downregulated genes respectively in the PD relative to control caudate, and  3108 and 2486 genes up and downregulated genes  in PD putamen compared to controls.   Pathways regulating synaptic signaling and plasticity, mitochondrial protein complex, autophagy and microRNA activity were altered in PD. Unfolded protein response, circadian rhythm, protein localization to endoplasmic reticulum and histone acetylation pathways were altered in the caudate in PDD.  1362  and 1934 alternatively spliced messenger RNA(mRNA)s were discovered in caudate and putamen respectively, encoding proteins involved in dendrite morphogenesis, neurogenesis and splicing, with some gene transcripts exclusively spliced in PD. We identified predicted RNA binding proteins regulating these splice events and their functional consequences on proteins in PD.

These observations define the striatal transcriptomic landscape in PD and PDD and provide evidence that dysregulation of mRNA splicing is a key feature of PD.