CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis
<p><strong>Background</strong></p> <p>Extracellular vesicles (EVs) released by neurons and glia reach the cerebrospinal fluid (CSF). Studying the proteome of CSF-derived EVs offers a novel perspective on the key intracellular processes associated with the pathogenesis o...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
BioMed Central
2020
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| _version_ | 1826305131878023168 |
|---|---|
| author | Thompson, AG Gray, E Mäger, I Thézénas, M-L Charles, PD Talbot, K Fischer, R Kessler, BM Wood, M Turner, MR |
| author_facet | Thompson, AG Gray, E Mäger, I Thézénas, M-L Charles, PD Talbot, K Fischer, R Kessler, BM Wood, M Turner, MR |
| author_sort | Thompson, AG |
| collection | OXFORD |
| description | <p><strong>Background</strong></p>
<p>Extracellular vesicles (EVs) released by neurons and glia reach the cerebrospinal fluid (CSF). Studying the proteome of CSF-derived EVs offers a novel perspective on the key intracellular processes associated with the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and a potential source from which to develop biomarkers.</p>
<p><strong>Methods</strong></p>
<p>CSF EVs were extracted using ultrafiltration liquid chromatography from ALS patients and controls. EV size distribution and concentration was measured using nanoparticle tracking analysis and liquid chromatography-tandem mass spectrometry proteomic analysis performed.</p>
<p><strong>Results</strong></p>
<p>CSF EV concentration and size distribution did not differ between ALS and control groups, nor between a sub-group of ALS patients with or without an associated hexanucleotide repeat expansion (HRE) in C9orf72. Univariate proteomic analysis identified downregulation of the pentameric proteasome-like protein Bleomycin hydrolase in ALS patients, whilst Gene Ontology enrichment analysis demonstrated downregulation of proteasome core complex proteins (8/8 proteins, normalized enrichment ratio -1.77, FDR-adjusted p = 0.057) in the ALS group. The sub-group of ALS patients associated with the C9orf72 HRE showed upregulation in Ubiquitin-like modifying-activating protein 1 (UBA1) compared to non-C9orf72 cases.</p>
<p><strong>Conclusions</strong></p>
<p>Proteomic analysis of CSF EVs in ALS detects intracellular alterations in protein homeostatic mechanisms, previously only identified in pathological tissues. This supports the wider use of CSF EVs as a source of novel biomarkers reflecting key and potentially druggable pathological intracellular pathway alterations in ALS.</p> |
| first_indexed | 2024-03-07T06:28:14Z |
| format | Journal article |
| id | oxford-uuid:f50f3d95-9124-4fb1-ae5a-e072c03126d0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:28:14Z |
| publishDate | 2020 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | oxford-uuid:f50f3d95-9124-4fb1-ae5a-e072c03126d02022-03-27T12:24:31ZCSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f50f3d95-9124-4fb1-ae5a-e072c03126d0EnglishSymplectic ElementsBioMed Central2020Thompson, AGGray, EMäger, IThézénas, M-LCharles, PDTalbot, KFischer, RKessler, BMWood, MTurner, MR<p><strong>Background</strong></p> <p>Extracellular vesicles (EVs) released by neurons and glia reach the cerebrospinal fluid (CSF). Studying the proteome of CSF-derived EVs offers a novel perspective on the key intracellular processes associated with the pathogenesis of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and a potential source from which to develop biomarkers.</p> <p><strong>Methods</strong></p> <p>CSF EVs were extracted using ultrafiltration liquid chromatography from ALS patients and controls. EV size distribution and concentration was measured using nanoparticle tracking analysis and liquid chromatography-tandem mass spectrometry proteomic analysis performed.</p> <p><strong>Results</strong></p> <p>CSF EV concentration and size distribution did not differ between ALS and control groups, nor between a sub-group of ALS patients with or without an associated hexanucleotide repeat expansion (HRE) in C9orf72. Univariate proteomic analysis identified downregulation of the pentameric proteasome-like protein Bleomycin hydrolase in ALS patients, whilst Gene Ontology enrichment analysis demonstrated downregulation of proteasome core complex proteins (8/8 proteins, normalized enrichment ratio -1.77, FDR-adjusted p = 0.057) in the ALS group. The sub-group of ALS patients associated with the C9orf72 HRE showed upregulation in Ubiquitin-like modifying-activating protein 1 (UBA1) compared to non-C9orf72 cases.</p> <p><strong>Conclusions</strong></p> <p>Proteomic analysis of CSF EVs in ALS detects intracellular alterations in protein homeostatic mechanisms, previously only identified in pathological tissues. This supports the wider use of CSF EVs as a source of novel biomarkers reflecting key and potentially druggable pathological intracellular pathway alterations in ALS.</p> |
| spellingShingle | Thompson, AG Gray, E Mäger, I Thézénas, M-L Charles, PD Talbot, K Fischer, R Kessler, BM Wood, M Turner, MR CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis |
| title | CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis |
| title_full | CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis |
| title_fullStr | CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis |
| title_full_unstemmed | CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis |
| title_short | CSF extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis |
| title_sort | csf extracellular vesicle proteomics demonstrates altered protein homeostasis in amyotrophic lateral sclerosis |
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