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01-12-2020 | Amyotrophic Lateral Sclerosis | Research

Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation

Authors: Anu Mary Varghese, Mausam Ghosh, Savita Kumari Bhagat, K. Vijayalakshmi, Veeramani Preethish-Kumar, Seena Vengalil, Pradeep-Chandra-Reddy Chevula, Saraswati Nashi, Kiran Polavarapu, Meenakshi Sharma, Rupinder Singh Dhaliwal, Mariamma Philip, Atchayaram Nalini, Phalguni Anand Alladi, Talakad N. Sathyaprabha, Trichur R. Raju

Published in: Journal of Neuroinflammation | Issue 1/2020

Abstract

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 motor neurons respectively after 48 h of injection. Levels of tumour necrosis factor-α and interleukin-6 were measured by ELISA.

Findings

CHIT-1 level in ALS-CSF samples was increased by 20-fold 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 15-fold higher in ALS-CSF and has a sensitivity of 80.4% and specificity of 80% at cut off value of 0.1077989 μmol/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 motor neurons.

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.

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Title: Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation
Authors: Anu Mary Varghese
Mausam Ghosh
Savita Kumari Bhagat
K. Vijayalakshmi
Veeramani Preethish-Kumar
Seena Vengalil
Pradeep-Chandra-Reddy Chevula
Saraswati Nashi
Kiran Polavarapu
Meenakshi Sharma
Rupinder Singh Dhaliwal
Mariamma Philip
Atchayaram Nalini
Phalguni Anand Alladi
Talakad N. Sathyaprabha
Trichur R. Raju
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Amyotrophic Lateral Sclerosis
Biomarkers
Published in: Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-020-01909-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Chitotriosidase, a biomarker of amyotrophic lateral sclerosis, accentuates neurodegeneration in spinal motor neurons through neuroinflammation

Abstract

Background

Methods

Findings

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Findings

Conclusions

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