Transcriptional Analysis of Nuclear-Encoded Mitochondrial Genes in Eight Neurodegenerative Disorders: The Analysis of Seven Diseases in Reference to Friedreich's Ataxia.

Muhammad Elsadany,Reem A Elghaish,Alaa S Ahmed,Aya S Khalil,Eman Badr,Menattallah Elserafy,Rana H Mansour

doi:10.3389/fgene.2021.749792

Abstract

Neurodegenerative diseases (NDDs) are challenging to understand, diagnose, and treat. Revealing the genomic and transcriptomic changes in NDDs contributes greatly to the understanding of the diseases, their causes, and development. Moreover, it enables more precise genetic diagnosis and novel drug target identification that could potentially treat the diseases or at least ease the symptoms. In this study, we analyzed the transcriptional changes of nuclear-encoded mitochondrial (NEM) genes in eight NDDs to specifically address the association of these genes with the diseases. Previous studies show strong links between defects in NEM genes and neurodegeneration, yet connecting specific genes with NDDs is not well studied. Friedreich’s ataxia (FRDA) is an NDD that cannot be treated effectively; therefore, we focused first on FRDA and compared the outcome with seven other NDDs, including Alzheimer’s disease, amyotrophic lateral sclerosis, Creutzfeldt–Jakob disease, frontotemporal dementia, Huntington’s disease, multiple sclerosis, and Parkinson’s disease. First, weighted correlation network analysis was performed on an FRDA RNA-Seq data set, focusing only on NEM genes. We then carried out differential gene expression analysis and pathway enrichment analysis to pinpoint differentially expressed genes that are potentially associated with one or more of the analyzed NDDs. Our findings propose a strong link between NEM genes and NDDs and suggest that our identified candidate genes can be potentially used as diagnostic markers and therapeutic targets.

Highlights

Neurodegenerative diseases (NDDs) are multifactorial disorders that are known to progress gradually with perceptible loss of neuronal function (Angelini et al, 2009)
Despite the complex nature of NDDs, continuous research efforts are directed toward finding a cure to halt the escalation of symptoms and provide a definitive treatment
We investigate the transcriptomic changes in nuclear-encoded mitochondrial (NEM) genes in Friedreich’s ataxia (FRDA) and seven other NDDs

Summary

Introduction

Neurodegenerative diseases (NDDs) are multifactorial disorders that are known to progress gradually with perceptible loss of neuronal function (Angelini et al, 2009). Even though recent studies conclude that mitochondrial dysfunction is a common overlapping feature between all neurodegenerative diseases, clear links between genes playing a role in mitochondrial function and NDDs are not well established (Huang et al, 2020). The remaining mitochondrial proteins are nuclear encoded (Neupert, 2015; Wiedemann and Pfanner, 2017). We compared the transcriptomic changes in nuclear-encoded mitochondrial (NEM) genes between FRDA and other seven NDDs in an attempt to identify common dysregulated genes and connect what is known about the diseases to FRDA. We discuss below some known links between the eight NDDs and mitochondrial dysfunction

Methods

Results

Discussion

Conclusion