Transcriptomic Signatures Associated With Regional Cortical Thickness Changes in Parkinson's Disease.

Arlin Keo,Jacobus J Van Hilten,Oleh Dzyubachyk,Marcel J T Reinders,Ahmed Mahfouz,Jeroen Van Der Grond

doi:10.3389/fnins.2021.733501

Arlin Keo, Jacobus J Van Hilten + Show 4 more

Open Access

https://doi.org/10.3389/fnins.2021.733501

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Abstract

Cortical atrophy is a common manifestation in Parkinson’s disease (PD), particularly in advanced stages of the disease. To elucidate the molecular underpinnings of cortical thickness changes in PD, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and patterns of cortical thickness based on T1-weighted anatomical MRI data of 149 PD patients and 369 controls. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of PD. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in PD are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in PD and possibly influence motor and cognitive functions.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic and non-dopaminergic neurons in the brain and peripheral and autonomic nervous system (Hirsch et al, 2012)
We applied Partial least squares (PLS) to assess the healthy transcriptome across the whole brain and find correlations with cortical thickness changes in PD, which can be observed as atrophy and hypertrophy patterns in neuroimaging data
We found genes that point toward pathways involved in cellular maintenance mechanisms that are well known in PD and other neurodegenerative diseases, but here we show that these pathways are differently regulated across brain regions

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic and non-dopaminergic neurons in the brain and peripheral and autonomic nervous system (Hirsch et al, 2012). The AHBA has been combined with functional MRI data of PD patients and revealed that the regional expression of MAPT, but not SNCA, correlated with the loss of regional connectivity (Rittman et al, 2016). Correlations were identified between a cortical atrophy pattern and the regional expression of 17 genes implicated in PD (Freeze et al, 2018). Both studies used spatial transcriptomics to explore gene expression across the whole brain, they only analyzed the expression of a limited set of genes that are of interest to PD, e.g., those that are known as genetic risk factors

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