Reduced mtDNA Copy Number in the Prefrontal Cortex of C9ORF72 Patients

Maria Isabel Alvarez-Mora,Laia Rodriguez-Revenga,Laura Molina-Porcel,Petar Podlesniy,Teresa Riazuelo,Ellen Gelpi

doi:10.1007/s12035-021-02673-7

Abstract

Hexanucleotide repeat expansion in C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Loss of C9ORF72 protein function and a toxic gain-of-function directly by the RNA or RAN translation have been proposed as triggering pathological mechanisms, along with the accumulation of TDP-43 protein. In addition, mitochondrial defects have been described to be a major driver of disease initiation. Mitochondrial DNA copy number has been proposed as a useful biomarker of mitochondrial dysfunction. The aim of our study was to determine the presence of mtDNA copy number alterations in C9ALS/FTD patients. Therefore, we assessed mtDNA copy number in postmortem prefrontal cortex from 18 C9ORF72 brain donors and 9 controls using digital droplet PCR. A statistically significant decrease of 50% was obtained when comparing C9ORF72 samples and controls. This decrease was independent of age and sex. The reduction of mtDNA copy number was found to be higher in patients' samples presenting abundant TDP-43 protein inclusions. A growing number of studies demonstrated the influence of mtDNA copy number reduction on neurodegeneration. Our results provide new insights into the role of mitochondrial dysfunction in the pathogenesis of C9ALS/FTD.

Highlights

IntroductionThe mechanisms of disease of C9ALS/frontotemporal dementia (FTD) remain unknown, three pathological mechanisms of C9ORF72 gene mutation have been described
In 2011, abnormal expansion of a GGGGCC (G4C2) hexanucleotid repeat in a non-coding region of the C9ORF72 gene was identified as the most common genetic cause of familial and sporadic forms of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD) [1, 2]. the mechanisms of disease of C9ALS/FTD remain unknown, three pathological mechanisms of C9ORF72 gene mutation have been described
We studied the mitochondrial DNA (mtDNA) copy number in postmortem prefrontal cortex obtained from 18 C9ALS/FTD patients compared to 9 control samples

Summary

Introduction

The mechanisms of disease of C9ALS/FTD remain unknown, three pathological mechanisms of C9ORF72 gene mutation have been described. Gain of function by repeat-associated non-ATG initiated (RAN) translation of dipeptide-repeat protein (DPR) from the sense and antisense strand [reviewed in 5]. ALS vs FTLD and correlates with the degree of degenerative changes [reviewed in 9] Of these features, DPR pathology and nuclear RNA foci are unique and highly specific to C9ALS/FTD. DPR pathology and nuclear RNA foci are unique and highly specific to C9ALS/FTD In addition to these three molecular mechanisms, many more downstream cellular pathways have been described to be affected in C9ALS/FTD, including nucleo-cytoplasmic transport, RNA processing, function of nucleolus, formation of membrane-less organelles, translation and ubiquitin proteasome system alterations, and DNA damage repair pathways impairment [reviewed in 5, 10]. Nowadays it is still unclear which molecular events initiate the disease

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