Dysregulated Gene Expression in Lymphoblasts from Parkinson’s Disease

Abstract

Parkinson’s disease is the second largest neurodegenerative disease worldwide and is caused by a combination of genetics and environment. It is characterized by the death of neurons in the substantia nigra of the brain but is not solely a disease of the brain, as it affects multiple tissues and organs. Studying Parkinson’s disease in accessible tissues such as skin and blood has increased our understanding of the disease’s pathogenesis. Here, we used lymphoblast cell lines generated from Parkinson’s disease patient and healthy age- and sex-matched control groups and obtained their whole-cell transcriptomes and proteomes. Our analysis revealed, in both the transcriptomes and the proteomes of PD cells, a global downregulation of genes involved in protein synthesis, as well as the upregulation of immune processes and sphingolipid metabolism. In contrast, we discovered an uncoupling of mRNA and protein expression in processes associated with mitochondrial respiration in the form of a general downregulation in associated transcripts and an upregulation in proteins. Complex V was different to the other oxidative phosphorylation complexes in that the levels of its associated transcripts were also lower, but the levels of their encoded polypeptides were not elevated. This may suggest that further layers of regulation specific to Complex V are in play.

Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers

“…Of note, a previous study reported a dramatically elevated basal mitochondrial respiration in iPD LCLs, which was observed independently of patient age, disease progression, and disease severity, suggesting an early and stable switch to a hyperactive state 56 . More recently, whole-cell transcriptomes and proteomes of iPD and healthy control LCLs showed downregulated transcripts for mitochondrial respiratory chain complexes but upregulated proteins, thereby suggesting that the elevated mitochondrial respiration observed in iPD LCLs is translationally regulated 57 . Interestingly, two studies performed in PRKN -mutant skin fibroblasts from PD patients also reported a higher mitochondrial respiratory rate compared to controls 58 , 59 .…”

Proteomics analysis of the p.G849D variant in neurexin 2 alpha may reveal insight into Parkinson’s disease pathobiology

“…Here, changes in translation could affect oxidative stress and the transport of neurotransmitters, thereby causing cells to be more susceptible to cell damage and death. In addition, a study on lymphoblasts generated from PD patients showed an overall downregulation of genes involved in protein synthesis ( Annesley et al, 2022 ). Thus, recent literature has shown that dysregulated synaptic translation and mitochondrial dysfunction are linked ( Kuzniewska et al, 2020 ), mitochondrial ribosomal proteins have been linked in a PD GWAS ( Billingsley et al, 2019 ), pathways related to ribosomes are enriched in an RNA-sequencing analysis of a PD cohort ( Hemmings et al, 2022 ), and that lymphoblasts generated from PD patients have dysregulated expression of genes involved in protein synthesis ( Annesley et al, 2022 ).…”