Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation
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 appr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnins.2022.885313/full |
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| author | Virginie Imbault Chiara Dionisi Gilles Naeije David Communi Massimo Pandolfo Massimo Pandolfo |
| author_facet | Virginie Imbault Chiara Dionisi Gilles Naeije David Communi Massimo Pandolfo Massimo Pandolfo |
| author_sort | Virginie Imbault |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T08:42:41Z |
| format | Article |
| id | doaj.art-5bcfdc9453c5447195b0e562d4ba20b9 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-04-12T08:42:41Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-5bcfdc9453c5447195b0e562d4ba20b92022-12-22T03:39:48ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2022-07-011610.3389/fnins.2022.885313885313Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and NeuroinflammationVirginie Imbault0Chiara Dionisi1Gilles Naeije2David Communi3Massimo Pandolfo4Massimo Pandolfo5Mass Spectrometry and Proteomics Laboratory/Platform, Institut de Recherche en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Brussels, BelgiumLaboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, BelgiumNeurology Service, Hôpital Erasme, Université Libre de Bruxelles, Brussels, BelgiumMass Spectrometry and Proteomics Laboratory/Platform, Institut de Recherche en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Brussels, BelgiumLaboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, BelgiumNeurology Service, Hôpital Erasme, Université Libre de Bruxelles, Brussels, BelgiumClinical 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.https://www.frontiersin.org/articles/10.3389/fnins.2022.885313/fullFriedreich Ataxiacerebrospinal fluidproteomicsneuroinflammationbiomarkerneurodegeneration |
| spellingShingle | Virginie Imbault Chiara Dionisi Gilles Naeije David Communi Massimo Pandolfo Massimo Pandolfo Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation Frontiers in Neuroscience Friedreich Ataxia cerebrospinal fluid proteomics neuroinflammation biomarker neurodegeneration |
| title | Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation |
| title_full | Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation |
| title_fullStr | Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation |
| title_full_unstemmed | Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation |
| title_short | Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation |
| title_sort | cerebrospinal fluid proteomics in friedreich ataxia reveals markers of neurodegeneration and neuroinflammation |
| topic | Friedreich Ataxia cerebrospinal fluid proteomics neuroinflammation biomarker neurodegeneration |
| url | https://www.frontiersin.org/articles/10.3389/fnins.2022.885313/full |
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