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Chitotriosidase, a biomarker of Amyotrophic Lateral Sclerosis accentuates neurodegeneration in spinal motor neurons through neuroinflammation.
Trichur R Raju
National Institute of Mental Health and Neuro Sciences
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7742-4050
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Journal of Neuroinflammation.
Background: Cerebrospinal fluid from Amyotrophic Lateral Sclerosis patients (ALS-CSF) induces neurodegenerative changes in motor neurons and gliosis in sporadic ALS models. Search for identification of toxic factor(s) in CSF revealed an enhancement in the level and enzyme activity of chitotriosidase (CHIT-1). Here, we have investigated its upregulation in a large cohort of samples and more importantly its role in ALS pathogenesis in a rat model.
Methods: CHIT-1 level in CSF samples from ALS (n=158), non-ALS (n=12) and normal (n=48) subjects were measured using ELISA. Enzyme activity was also assessed (ALS, n=56; non-ALS, n=10 and normal-CSF, n=45). Recombinant CHIT-1 was intrathecally injected into Wistar rat neonates. Lumbar spinal cord sections were stained for Iba1, Glial Fibrillary Acidic Protein and Choline Acetyl Transferase to identify microglia, astrocytes and motorneurons respectively after 48hrs of injection. Levels of tumor necrosis factor-α and interleukin-6 was measured by ELISA.
Findings: CHIT-1 level in ALS-CSF samples was increased by twenty folds and it can distinguish ALS patients with a sensitivity of 87% and specificity of 83·3% at a cut off level of 1405·43 pg/ml. Enzyme activity of CHIT-1 was also fifteen folds higher in ALS-CSF and has a sensitivity of 80·4% and specificity of 80% at cut off value of 0·1077989μmol/μl/min. Combining CHIT-1 level and activity together gave a positive predictive value of 97·78% and negative predictive value of 100%. Administration of CHIT-1 increased microglial numbers and astrogliosis in the ventral horn with a concomitant increase in the levels of pro-inflammatory cytokines. Amoeboid shaped microglial and astroglial cells were also present around the central canal. CHIT-1 administration also resulted in the reduction of motorneurons.
Conclusions: CHIT-1, an early diagnostic biomarker of sporadic ALS activates glia priming them to attain a toxic phenotype resulting in neuroinflammation leading to motor neuronal death.
Keywords
Chitotriosidase, Amyotrophic Lateral Sclerosis, biomarker, neuroinflammation, glia, neurodegeneration
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Rashmi S.
commented on 04 June, 2020
A very well structured study that explores the role of Chitotriosidase in a large cohort of patient CSF samples while also giving an idea about the 'in-vivo' scenario. Unraveling the role of this intriguing enzyme in the pathomechanism of ALS , especially keeping in view the 'neuroinflammation' aspect, seems to have a promising future.
Shruthi Shanmukha
commented on 08 June, 2020
Accurate and early diagnosis is the key to manage any disease. This group was the first to report chit-1 as a potential biomarker for ALS, further validates its specificity and sensitivity in a large cohort size in this study. The study also unveils the neuro-inflammatory role of chit-1, providing an opportunity for future therapeutic interventions. Very well conducted study.
View 1 reply
Lynn scott
commented on 28 July, 2020
My Mom has had ALS for almost 3 years now, so I can relate heavily. I was getting so depressed and suicidal due to her illness that I had to move out. I visit her 4 times a week and sleep over 2 nights. This is the time you need to spend with him because you will regret it if you don’t. My mom has this computer that tracks her eye movements and she will blink on a letter which she can then form words with and the computer will say it out loud. Would you ever consider something like that? so luckily we found someone who cured her finally and deliver my mom from ALS. I will advice you give it a try to see the outcome. please try to contact them if you need their help [email protected]
eric
commented on 28 July, 2020
great news
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Review #2 received
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Review #1 received
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Reviewer #2 agreed
On 04 Feb, 2020
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On 01 Feb, 2020
Reviewers invited
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This preprint is under consideration at Journal of Neuroinflammation. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Chitotriosidase, a biomarker of Amyotrophic Lateral Sclerosis accentuates neurodegeneration in spinal motor neurons through neuroinflammation.
Trichur R Raju
National Institute of Mental Health and Neuro Sciences
Corresponding Author
ORCiD: https://orcid.org/0000-0002-7742-4050
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Version 2
Posted 02 Jun, 2020
Published
On 06 Aug, 2020
Community comments: 5
Editorial decision: Major Revision
On 18 Jun, 2020
Review #3 received
Received 12 Jun, 2020
Review #2 received
Received 12 Jun, 2020
Reviewer #2 agreed
On 29 May, 2020
Reviewer #3 agreed
On 29 May, 2020
Reviewer #1 agreed
On 28 May, 2020
Review #1 received
Received 28 May, 2020
Reviewers invited
Invitations sent on 27 May, 2020
Editor assigned
On 26 May, 2020
Submission checks complete
On 25 May, 2020
Editor invited
On 25 May, 2020
Community comments: 1
Editorial decision: Major Revision
On 02 Apr, 2020
Review #3 received
Received 27 Mar, 2020
Review #2 received
Received 26 Mar, 2020
Reviewer #3 agreed
On 09 Mar, 2020
Review #1 received
Received 24 Feb, 2020
Reviewer #2 agreed
On 04 Feb, 2020
Reviewer #1 agreed
On 01 Feb, 2020
Reviewers invited
Invitations sent on 18 Jan, 2020
Editor invited
On 15 Jan, 2020
First submitted
On 14 Jan, 2020
Editor assigned
On 14 Jan, 2020
Submission checks complete
On 13 Jan, 2020
Metrics
Comments: 5
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at Journal of Neuroinflammation.
Background: Cerebrospinal fluid from Amyotrophic Lateral Sclerosis patients (ALS-CSF) induces neurodegenerative changes in motor neurons and gliosis in sporadic ALS models. Search for identification of toxic factor(s) in CSF revealed an enhancement in the level and enzyme activity of chitotriosidase (CHIT-1). Here, we have investigated its upregulation in a large cohort of samples and more importantly its role in ALS pathogenesis in a rat model.
Methods: CHIT-1 level in CSF samples from ALS (n=158), non-ALS (n=12) and normal (n=48) subjects were measured using ELISA. Enzyme activity was also assessed (ALS, n=56; non-ALS, n=10 and normal-CSF, n=45). Recombinant CHIT-1 was intrathecally injected into Wistar rat neonates. Lumbar spinal cord sections were stained for Iba1, Glial Fibrillary Acidic Protein and Choline Acetyl Transferase to identify microglia, astrocytes and motorneurons respectively after 48hrs of injection. Levels of tumor necrosis factor-α and interleukin-6 was measured by ELISA.
Findings: CHIT-1 level in ALS-CSF samples was increased by twenty folds and it can distinguish ALS patients with a sensitivity of 87% and specificity of 83·3% at a cut off level of 1405·43 pg/ml. Enzyme activity of CHIT-1 was also fifteen folds higher in ALS-CSF and has a sensitivity of 80·4% and specificity of 80% at cut off value of 0·1077989μmol/μl/min. Combining CHIT-1 level and activity together gave a positive predictive value of 97·78% and negative predictive value of 100%. Administration of CHIT-1 increased microglial numbers and astrogliosis in the ventral horn with a concomitant increase in the levels of pro-inflammatory cytokines. Amoeboid shaped microglial and astroglial cells were also present around the central canal. CHIT-1 administration also resulted in the reduction of motorneurons.
Conclusions: CHIT-1, an early diagnostic biomarker of sporadic ALS activates glia priming them to attain a toxic phenotype resulting in neuroinflammation leading to motor neuronal death.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Rashmi S.
commented on 04 June, 2020
A very well structured study that explores the role of Chitotriosidase in a large cohort of patient CSF samples while also giving an idea about the 'in-vivo' scenario. Unraveling the role of this intriguing enzyme in the pathomechanism of ALS , especially keeping in view the 'neuroinflammation' aspect, seems to have a promising future.
Shruthi Shanmukha
commented on 08 June, 2020
Accurate and early diagnosis is the key to manage any disease. This group was the first to report chit-1 as a potential biomarker for ALS, further validates its specificity and sensitivity in a large cohort size in this study. The study also unveils the neuro-inflammatory role of chit-1, providing an opportunity for future therapeutic interventions. Very well conducted study.
View 1 reply
Pooja
replied on 08 June, 2020
Rightly said. Many studies have followed and validated these results.Yet the mechanism for Chit-1 and clinical correlations were missing. This study adds relevant information to the literature.
Lynn scott
commented on 28 July, 2020
My Mom has had ALS for almost 3 years now, so I can relate heavily. I was getting so depressed and suicidal due to her illness that I had to move out. I visit her 4 times a week and sleep over 2 nights. This is the time you need to spend with him because you will regret it if you don’t. My mom has this computer that tracks her eye movements and she will blink on a letter which she can then form words with and the computer will say it out loud. Would you ever consider something like that? so luckily we found someone who cured her finally and deliver my mom from ALS. I will advice you give it a try to see the outcome. please try to contact them if you need their help [email protected]
eric
commented on 28 July, 2020
great news
Pooja
replied on 08 June, 2020
Rightly said. Many studies have followed and validated these results.Yet the mechanism for Chit-1 and clinical correlations were missing. This study adds relevant information to the literature.