Quantitative profiling and identification of differentially expressed plasma proteins in friedreich's ataxia

Abstract

Friedreich's ataxia (FRDA) is an autosomal recessive ataxia, characterized by progressive gait ataxia, limb ataxia, dysarthria, and areflexia associated with diabetes and hypertrophic cardiomyopathy. The primary cause of FRDA is the presence of expanded DNA triplet (GAA) repeats in the first intron of the fxn gene on chromosome 9q13. The expanded DNA repeats in fxn inhibit expression of the protein frataxin, which leads to neuronal degeneration. The aim of the study was to identify differentially expressed plasma proteins in FRDA patients for their diagnostic/prognostic applications. Clinically suspected FRDA patients (n = 42) were assessed on the International Co-Operative Ataxia Rating Scale (ICARS), and genetic confirmation was performed by analyzing (GAA) repeats via PCR. Eighteen patients were confirmed to be homozygous for FRDA, with ICARS scores of 40 ± 8. Plasma proteomics of homozygous FRDA patients and age- and gender-matched healthy controls was done using two-dimensional difference in-gel electrophoresis and LC-MS/MS. Quantitative proteomic analysis (fold change ≥1.5; P < 0.05) revealed 13 differentially expressed protein spots. These proteins were found to be associated with neuropathy (α1-antitrypsin), ataxia (apolipoprotein A-I), oxidative stress (albumin), altered lipid metabolism (apolipoprotein C-II, C-III), etc. Further investigations of these differentially expressed proteins can aid in identifying prognostic/diagnostic markers for FRDA.

Oxidative stress in inherited mitochondrial diseases

“…Similar studies observed increased nuclear and mitochondrial DNA damage in FA patient peripheral blood cells and elevation of albumin, a marker of oxidative damage in blood plasma of patients [36, 37]. Activities of antioxidative enzymes and molecules are also indicated to be reduced in frataxin deficient patients and animal models.…”

Impact of Drosophila Models in the Study and Treatment of Friedreich’s Ataxia

“…In short, two main manifestations of such redox alterations are present in the FRDA literature. On one hand, loss of frataxin function triggers the production of oxidative stress biomarkers in yeast [ 6 , 108 , 118 , 119 , 120 , 121 , 122 ], C. elegans [ 123 ], mouse [ 25 , 95 ] as well as in FRDA patients and patients-derived samples [ 97 , 115 , 122 , 124 , 125 , 126 , 127 , 128 , 129 ]. On the other hand, frataxin deficient cells have been shown to display increased sensitivity towards antioxidant insult [ 97 , 98 ].…”

“…Although the lipid accumulation found in the FRDA flies seems to differ from the pathological features found in postmortem analysis of FRDA patients [ 163 ], several indications suggest lipid dyshomeostasis in the patients [ 129 , 164 , 165 , 166 , 167 , 168 ]. Since this fly report from Navarro et al [ 63 ], the accumulation of lipids has been reported in mouse, rat and human cell culture FRDA models [ 169 , 170 , 171 ] and remodeling of lipid metabolism has been observed in C. elegans [ 172 ].…”

Degenerative Ataxias: challenges in clinical research

“…Similarly, accurate measurements of various ataxin levels may be useful for treatment strategies aimed at “knocking down” the gene. Others have reported on plasma protein profiling, oxidative markers, and microRNAs …”