Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

Cerebrospinal fluid (CSF) has been implicated in amyotrophic lateral sclerosis (ALS) due to its ability to spread inflammatory proteins throughout the nervous system. We hypothesized that filtration of the CSF could remove pathogenic proteins and prevent them from altering motor phenotypes in a mous...

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Veröffentlicht in:Curēus (Palo Alto, CA) CA), 2022-12, Vol.14 (12), p.e32980-e32980
Hauptverfasser: Venkatraman, Vishal, Filiano, Anthony J, Xu, Li, Collins, Leonard, Luo, Emily, Ripple, Katelyn M, de Castro, George C, Boua, Jane-Valeriane K, Marius, Choiselle, Giamberardino, Charles, Lad, Shivanand P, Islam Williams, Taufika, Bereman, Michael S, Bedlack, Richard S
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container_title Curēus (Palo Alto, CA)
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creator Venkatraman, Vishal
Filiano, Anthony J
Xu, Li
Collins, Leonard
Luo, Emily
Ripple, Katelyn M
de Castro, George C
Boua, Jane-Valeriane K
Marius, Choiselle
Giamberardino, Charles
Lad, Shivanand P
Islam Williams, Taufika
Bereman, Michael S
Bedlack, Richard S
description Cerebrospinal fluid (CSF) has been implicated in amyotrophic lateral sclerosis (ALS) due to its ability to spread inflammatory proteins throughout the nervous system. We hypothesized that filtration of the CSF could remove pathogenic proteins and prevent them from altering motor phenotypes in a mouse model. We filtered the CSF from 11 ALS patients via 100 kilodaltons (kD) molecular weight cut-off filters. We used mass spectrometry-based discovery proteomics workflows to compare protein abundances before and after filtration. To test the effects of CSF filtration on motor function, we injected groups of mice with saline, filtered ALS-CSF, or unfiltered ALS-CSF (n=12 per group) and assessed motor function via pole descent and open field tests. We identified proteins implicated in ALS pathogenesis and showed that these were removed in significant amounts in our workflow. Key filtered proteins included complement proteins, chitinases, serine protease inhibitors, and neuro-inflammatory proteins such as amyloid precursor protein, chromogranin A, and glial fibrillary acidic protein. Compared to the filtered ALS-CSF mice, unfiltered ALS-CSF mice took longer to descend a pole (10 days post-injection, 11.14 seconds vs 14.25 seconds, p = 0.02) and explored less on an open field (one day post-injection, 21.81 m vs 16.83 m, p = 0.0004). We demonstrated the ability to filter proteins from the CSF of ALS patients and identified potentially pathologic proteins that were reduced in quantity. Additionally, we demonstrated the ability of unfiltered ALS-CSF to induce motor deficits in mice on the pole descent and open field tests and showed that filtration could prevent this deficit. Given the lack of effective treatments for ALS, this could be a novel solution for patients suffering from this deadly and irreversible condition.
doi_str_mv 10.7759/cureus.32980
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We hypothesized that filtration of the CSF could remove pathogenic proteins and prevent them from altering motor phenotypes in a mouse model. We filtered the CSF from 11 ALS patients via 100 kilodaltons (kD) molecular weight cut-off filters. We used mass spectrometry-based discovery proteomics workflows to compare protein abundances before and after filtration. To test the effects of CSF filtration on motor function, we injected groups of mice with saline, filtered ALS-CSF, or unfiltered ALS-CSF (n=12 per group) and assessed motor function via pole descent and open field tests. We identified proteins implicated in ALS pathogenesis and showed that these were removed in significant amounts in our workflow. Key filtered proteins included complement proteins, chitinases, serine protease inhibitors, and neuro-inflammatory proteins such as amyloid precursor protein, chromogranin A, and glial fibrillary acidic protein. Compared to the filtered ALS-CSF mice, unfiltered ALS-CSF mice took longer to descend a pole (10 days post-injection, 11.14 seconds vs 14.25 seconds, p = 0.02) and explored less on an open field (one day post-injection, 21.81 m vs 16.83 m, p = 0.0004). We demonstrated the ability to filter proteins from the CSF of ALS patients and identified potentially pathologic proteins that were reduced in quantity. Additionally, we demonstrated the ability of unfiltered ALS-CSF to induce motor deficits in mice on the pole descent and open field tests and showed that filtration could prevent this deficit. 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subjects Amyotrophic lateral sclerosis
Biobanks
Cerebrospinal fluid
Guillain-Barre syndrome
Mass spectrometry
Medical research
Patients
Peptides
Proteins
Proteomics
Review boards
Scientific imaging
title Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model
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