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Oligodendroglia Confer Neuroprotection to NSC-34 Motor Neuronal Cells Against the Toxic Insults of Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients

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Abstract

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder with multifactorial pathomechanisms affecting not only motor neurons but also glia. Both astrocytes and microglia get activated and contribute significantly to neurodegeneration. The role of oligodendroglia in such a situation remains obscure, especially in the sporadic form of ALS (SALS), which contributes to 90% of cases. Here, we have investigated the role of oligodendroglia in SALS pathophysiology using a human oligodendroglial cell line, MO3.13, by exposing the cells to cerebrospinal fluid from SALS patients (ALS-CSF; 10% v/v for 48 h). ALS-CSF significantly reduced the viability of MO3.13 cells and down-regulated the expression of oligodendroglia-specific proteins, namely, CNPase and Olig2. Furthermore, to investigate the effect of the observed oligodendroglial changes on motor neurons, NSC-34 motor neuronal cells were co-cultured/supplemented with conditioned/spent medium of MO3.13 cells upon exposure to ALS-CSF. Live cell imaging experiments revealed protection to NSC-34 cells against ALS-CSF toxicity upon co-culture with MO3.13 cells. This was evidenced by the absence of neuronal cytoplasmic vacuolation and beading of neurites, which instead resulted in better neuronal differentiation. Enhanced lactate levels and increased expression of its transporter, MCT-1, with sustained expression of trophic factors, namely, GDNF and BDNF, by MO3.13 cells hint towards metabolic and trophic support provided by the surviving oligodendroglia. Similar metabolic changes were seen in the lumbar spinal cord oligodendroglia of rat neonates intrathecally injected with ALS-CSF. The findings indicate that oligodendroglia are indeed rescuer to the degenerating motor neurons when the astrocytes and microglia turn topsy-turvy.

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Acknowledgements

We thank the National Institute of Mental Health and Neurosciences, Bengaluru, for providing M.Phil. Fellowship to Ramya V. and Nisha Sarkar. Anu Mary Varghese and Savita Bhagat were Fellows in the ICMR-CAR funded project (Indian Council for Medical Research – Centre for Advanced Research, Govt. of India). Raj Kumar Pradhan was a JRF in a DBT-BioCARe funded project (Department of Biotechnology, Govt. of India). We acknowledge Sandeep Rajkumar, JRF in the SERB-ECR funded project (Science and Engineering Research Board, Govt. of India) for his contribution in designing the co-culture experiments with appropriate live cell imaging dyes.

Funding

This work was funded by the SERB-EEQ project (Science and Engineering Research Board, Department of Science and Technology, Govt. of India; Project Sanction No. EEQ/2020/000625) to Dr. Vijayalakshmi K. and ICMR A.S. Paintal Distinguished Scientist Chair Grant (Indian Council for Medical Research, Govt. of India) to Dr. T. R. Raju.

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Author notes

  1. V. Ramya, Nisha Sarkar, and Savita Bhagat equally contributed to this work.

Authors and Affiliations

  1. Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Hosur Road, Bengaluru, 560 029, India

    V. Ramya, Nisha Sarkar, Savita Bhagat, Raj Kumar Pradhan, Anu Mary Varghese, Talakad N. Sathyaprabha, Trichur R. Raju & K. Vijayalakshmi

  2. Department of Neurology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Hosur Road, Bengaluru, 560 029, India

    Atchayaram Nalini

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  6. Atchayaram Nalini
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  7. Talakad N. Sathyaprabha
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  8. Trichur R. Raju
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  9. K. Vijayalakshmi
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by V. Ramya, Nisha Sarkar, Savita Bhagat, Raj Kumar Pradhan, Anu Mary Varghese, and K. Vijayalakshmi. Patients were recruited for the study by Dr. Atchayaram Nalini. The first draft of the manuscript was written by V. Ramya, Nisha Sarkar, T.R. Raju, and K. Vijayalakshmi, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to K. Vijayalakshmi.

Ethics declarations

Ethics Approval and Consent to Participate

CSF samples were collected after approval of the human ethics committee, and informed consent was taken prior to CSF collection (No. NIMHANS/91st IEC/ 2014/ (Item no. III, SI no. 3.01, Basic Sciences). All animal experiments were approved by the Institutional Animal Ethics Committee (IAEC), NIMHANS, Bangalore (IAEC Approval No. AEC/67/423/N.P).

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Not applicable, as no individual participant’s data is presented.

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The authors declare no competing interests.

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Supplementary Information

ESM 1

Online Resource 1a and b: Live cell imaging videos of NSC-34 cells grown under normal conditions and exposed to ALS-CSF a, NSC-34 cells under normal conditions appeared well differentiated with pleomorphic morphology bearing processes. By 48hrs, most of the cells remained differentiated except a few which were undifferentiated with round morphology appeared to be clumped. b, Exposure to ALS-CSF caused dedifferentiation of most of the NSC-34 cells with retraction of processes and attaining rounded morphology with marked clumping and formation of apoptotic bodies in a few cells. Toxicity of ALS-CSF resulted in degeneration of NSC-34 cells similar to our findings (Vijayalakshmi et al., 2009). (ZIP 8481 kb)

ESM 2

Online Resource 2a, b, c and d, e, f: Live cell imaging videos of co-culture of MO3.13 cells (Red) with NSC-34 cells (Green) grown under normal conditions and exposed to NALS-CSF and ALS-CSF Live cell imaging of NSC-34 motor neuronal cells (CMFDA; Green) and MO3.13 oligodendroglial cells (CM-DiI; Red) in co-culture from 0-24hrs (a - NC, b - NALS, c - ALS) and 24-48hrs (d - NC, e – NALS, f - ALS). NSC-34 cells differentiated well with long processes and appeared similar to the cells grown under normal conditions (Compare c Video clip with a, b and f with d, e). There was no characteristic features of degeneration or dedifferentiation of NSC-34 cells even in the presence of ALS-CSF upon co-culture with MO3.13 cells indicating neuroprotection conferred by the oligodendroglial cells. (ZIP 165953 kb)

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Ramya, V., Sarkar, N., Bhagat, S. et al. Oligodendroglia Confer Neuroprotection to NSC-34 Motor Neuronal Cells Against the Toxic Insults of Cerebrospinal Fluid from Sporadic Amyotrophic Lateral Sclerosis Patients. Mol Neurobiol 60, 4855–4871 (2023). https://doi.org/10.1007/s12035-023-03375-y

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