Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation

Abstract

Clinical trials in rare diseases as Friedreich ataxia (FRDA) offer special challenges, particularly when multiple treatments become ready for clinical testing. Regulatory health authorities have developed specific pathways for “orphan” drugs allowing the use of a validated biomarker for initial approval. This study aimed to identify changes in cerebrospinal fluid (CSF) proteins occurring in FRDA patients that may be potential biomarkers in therapeutic trials. CSF was obtained from 5 FRDA patients (4 females, 1 male) from the Brussels site of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS). Two patients were ambulatory, three used a wheelchair. Residual CSF samples from 19 patients who had had a lumbar puncture as part of a diagnostic workup were used as controls. All CSF samples had normal cells, total protein and glucose levels. Proteins were identified by label-free data-dependent acquisition mass spectrometry (MS) coupled to micro-high performance liquid chromatography. We found 172 differentially expressed proteins (DEPs) (92 up, 80 down) between FRDA patients and controls at P < 0.05, 34 DEPs (28 up, 6 down) at P < 0.0001. Remarkably, there was no overlap between FRDA patients and controls for seven upregulated and six downregulated DEPs. Represented pathways included extracellular matrix organization, signaling, the complement cascade, adhesion molecules, synaptic proteins, neurexins and neuroligins. This study supports the hypothesis that the quantitative analysis CSF proteins may provide robust biomarkers for clinical trials as well as shed light on pathogenic mechanisms. Interestingly, DEPs in FA patients CSF point to neurodegeneration and neuroinflammation processes that may respond to treatment.

Length biases in single-cell RNA sequencing of pre-mRNA

“…Egln1 is linked to neuronal apoptosis ( 42 ). Fam174a is involved in lipid metabolism and membrane structure ( 43 ). Rnf152 and Rgmb are broadly implicated in neural development ( 44 , 45 , 46 ).…”

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich’s ataxia

“…Up to date, few proteomics studies have been conducted in FRDA patients derived tissues, namely in lymphocytes (Télot et al, 2018), fibroblasts (Napierala et al, 2021), cerebrospinal fluid (Imbault et al, 2022), and in iPSC-derived proprioceptors enriched neuronal cultures (Dionisi et al, 2023). Clinically nonaffected cells, such as FRDA patients-derived lymphocytes and fibroblasts, displayed milder changes in mitochondrial proteome and, interestingly, a much stronger downregulation of frataxin (Télot et al, 2018;Napierala et al, 2021).…”

Mapping Novel Frataxin Mitochondrial Networks Through Protein- Protein Interactions

“…They found that treatment Affi_224 was able to increase cysteine NSF1 desulfurase activation in the context of specific FXN mutants 32 . Other proteomics approaches have also been used to identify differences in cerebral spinal fluids of FRDA and control patients and several pathways associated with oxidation and inflammation were differentially regulated 33 .…”