Quantitative Proteomic and Network Analysis of Differentially Expressed Proteins in PBMC of Friedreich’s Ataxia (FRDA) Patients

Abstract

Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded (GAA) trinucleotide repeat in the FXN gene. The extended repeats expansion results in reduced transcription and, thereby, decreased expression of the mitochondrial protein, frataxin. Given the ongoing drug trials, identification of reliable and easily accessible biomarkers for monitoring disease progression and therapeutic intervention is a foremost requirement. In this study, comparative proteomic profiling of PBMC proteins from FRDA patients and age- and gender-matched healthy controls was done using 2D-Differential in-Gel Electrophoresis (2D-DIGE). Protein–protein interaction (PPI) was analyzed using BioGRID and STRING pathway analysis tools. Using biological variance analysis (BVA) and LC/MS, we found eight differentially expressed proteins with fold change ≥1.5; p ≤ 0.05. Based on their cellular function, the identified proteins showed a strong pathological role in neuroinflammation, cardiomyopathy, compromised glucose metabolism, and iron transport, which are the major clinical manifestations of FRDA. Protein–protein network analysis of differentially expressed proteins with frataxin further supports their involvement in the pathophysiology of FRDA. Considering their crucial role in the cardiac and neurological complications, respectively, the two down-regulated proteins, actin α cardiac muscle 1 (ACTC1) and pyruvate dehydrogenase E1 component subunit β (PDHE1), are suggested as potential prognostic markers for FRDA.

Detecting Brain Structure-Specific Methylation Signatures and Rules for Alzheimer’s Disease

“…Two other parameters that target HNRNPUL2 and FAM38A are functionally correlated with AD. Hypermethylation of these genes has also been demonstrated to participate in the development of diseases associated with nerve disorders ( Pathak et al, 2019 ; Gürkan et al, 2020 ) but not with AD. Therefore, these quantitative rules in the CRB were explained according to publications above, demonstrating the effectiveness of our analysis.…”

Reverse Phase Protein Array Reveals Correlation of Retinoic Acid Metabolism With Cardiomyopathy in Friedreich's Ataxia

“…Thus far, only a few proteomics studies were reported using FRDA patient–derived material, performed using small numbers of patient samples and using MS-based approaches ( 15 , 16 , 17 , 18 ). Here, for the first time, we compared protein expression signatures of a large cohort of FRDA primary fibroblasts, known to express molecular hallmarks of the disease, with a representative group of age- and sex-matched CTRL cells.…”

“…Thus, identifying DE proteins of lower abundance may be hampered. A few MS-based proteomics studies have been completed thus far in FRDA with limited numbers of samples and predominantly focused on differences between FRDA and CTRL cohorts ( 15 , 16 , 17 , 18 ).…”

Human peripheral blood mononuclear cells: A review of recent proteomic applications

“…For example, in the 2 studies investigating the PBMCs exposure to low dose radiation [32, 33], there were seven proteins or almost half of the proposed candidates in each of the studies that overlapped between the studies exhibiting great reproducibility. Similarly, two studies investigating sepsis [18–35] and those investigating diabetes and tuberculosis‐diabetes co‐pathogenesis [11–20], also identified mutual candidates. The most promising PBMCs biomarker based on specificity and validation approaches performed, are marked with red circles in Figure 4.…”

“…After recognition of antigen/body intruder, PBMCs turn from naïve/resting to state, undergoing differentiation and development of effector functions [8][9][10]. Changes associated with inflammation [11], immune-mediated inflammationautoimmune disorders [12,13], genetic pathology towards neurodegeneration [14], mental disorder alternations [15,16], cancer progression [10] or virus-hosting-SARS-CoV-2 pathogenesis [17], are to name a few.…”