A Computational Analysis in a Cohort of Parkinson’s Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes

Abstract

Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in DBP, GBA, TEF, SNCA, SERPINA1 and TGFB1. Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., HRAS and GBA) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., TUBB6, PAK6, SLC11A1).

Skeletal muscle gene expression dysregulation in long-term spaceflights and aging is clock-dependent

“…reported among patients as compared to the healthy control groups 99 . This highlight potential implications of spaceflights in neurodegeneration and further research in this direction will be needed.…”

It’s About Time: The Circadian Network as Time-Keeper for Cognitive Functioning, Locomotor Activity and Mental Health

“…Recently, a time course analysis using human colorectal cancer (CRC) cells with distinct clock phenotypes pointed to a link between cancer and neurodegenerative diseases involving the circadian system, and suggested the differential enrichment of genes involved in HD, AD and PD ( Yalcin et al, 2020 ). In a follow-up study, the KO of core-clock genes in CRC cell lines was shown to disrupt rhythmic expression of cancer and neurodegeneration-related genes and led to similar alterations at the mean gene expression level, as observed in a cohort of PD patients compared to healthy controls ( Yalcin et al, 2021 ). Circadian disturbances are among the earliest symptoms of neurodegenerative diseases such as HD, AD, and PD, and malfunctioning in the molecular mechanisms of the circadian system is thought to play a pivotal, and possibly even causal, role in their pathological development ( Hood and Amir, 2017b ; Carter et al, 2021 ).…”

“…In a recent bioinformatics study pointing to molecular clock dysfunction in PD ( Yalçin et al, 2021 ), PD patients exhibited weaker correlations in the expression of clock genes than in age and sex matched controls. In a normally functioning cell or organism, expression of clock genes is tightly ruled by intricated feedback loops and entrained by the master clock in the SCN.…”

Antiproliferative Effects of Cynara Cardunculus in Colorectal Cancer Cells Are Modulated by the Circadian Clock

“…HCT116 core-clock KO cell lines were generated as previously described [ 42 , 43 ]. In short, HCT116 WT cells were transfected with CRISPR-Cas9 plasmids and guide RNAs targeting core-clock genes BMAL1 , PER2 or NR1D1 .…”