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

Autor: Varghese AM; Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Ghosh M; Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Bhagat SK; Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Vijayalakshmi K; Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Preethish-Kumar V; Department of Clinical Neuroscience, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Vengalil S; Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Chevula PC; Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Nashi S; Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Polavarapu K; Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Sharma M; Division of Non Communicable Disease, Indian Council of Medical Research, New Delhi, India., Dhaliwal RS; Division of Non Communicable Disease, Indian Council of Medical Research, New Delhi, India., Philip M; Department of Biostatistics, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Nalini A; Department of Neurology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Alladi PA; Department of Clinical Pharmacology & Neurotoxicology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Sathyaprabha TN; Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India., Raju TR; Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences, Hosur Road, Bengaluru, 560 029, India. trraju.nimhans@gmail.com.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2020 Aug 06; Vol. 17 (1), pp. 232. Date of Electronic Publication: 2020 Aug 06.
DOI: 10.1186/s12974-020-01909-y
Abstrakt: 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.
Databáze: MEDLINE
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