Profiling of the pathophysiological mediators of a rare neurodegenerative disease, Friedreich's Ataxia (FRDA)

Introduction

Friedreich's ataxia is a neuro-degenerative, autosomal recessive disease, which is clinically characterized by loss of coordination, ataxia, along with cardiomyopathy, scoliosis, and an increased risk of diabetes [1]. The disease is manifested due to a GAA expansion mutation on the intron of FXN gene, resulting in a reduction of functional frataxin in cells [2]. The project aims to identify the unknown pathophysiological mediators involved in the genesis and progression of Friedreich ataxia along with generating a proteomic profile of the patients.

Method

The samples were split into four major cohorts of healthy, patient, fibrotic patient, and non-fibrotic patients. Proteins from the plasma and urine samples were separated with gel-electrophoresis. Mass spectrometry (MS1 & MS2) analyses were performed to determine the proteomic profile of the samples with the Mascot Search Engine. A targeted MS analysis focused was conducted by focusing on frataxin and Neurofilament light chain (NFL) in sample cohorts.

Result

The patient cohort's frataxin level was reduced compared to the healthy cohort (Figure 1, A). However, there was no significant change in frataxin levels between the fibrotic and non-fibrotic patients (Figure 1, B). Finally, frataxin was detected in urine (Figure 1, C) at a reduced level compared to plasma.

NFL level had been increased in almost all FRDA patients, except for five patients (Figure 1, D). There was also no significant change in the NFL level between the fibrotic and non-fibrotic patients (Figure 1, E). NFL was also detected in urine (Figure 1, F) and the protein level was lower compared to the plasma NFL level.

Discussion

Frataxin reduction in the patient cohort correlates with the notion that FRDA is a frataxin deficiency disease [3]. An increase in NFL in most of the patients indicated increased axonal damage associated with the disease. The relatively lower NFL in five samples can be because the NFL level stabilizes toward the later stage of a neurodegenerative disease even though it increases during the early phase of the disease [4]. None of the frataxin and NFL had a significant difference between the fibrotic and non-fibrotic cohorts indicating irrelevance of these proteins to fibrosis progression. The detection of frataxin and NFL in the urine, albeit at a reduced level, was one of the most interesting findings, as no prior literature article describes this phenomenon. Focusing on this might lead to a new revelation associated with the pathophysiology of the FRDA disease.

References

1. Lynch et al, J. Multidiscip. Healthc., pp.1645-1658, 2021.

2. Gavriilaki et al, The Cerebellum, 1-20, 2023.

3. Doni et al, Cell Death Dis, 14(12), p.805, 2023.

4. Zhang et al, Front Neurol., 13, p.833507, 2022.