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Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive degeneration of motor neurons leading to skeletal muscle denervation. Earlier studies have shown that motor neuron degeneration begins in motor cortex and descends to the neuromuscular junction (NMJ) in a dying forward fashion. However, accumulating evidences support that ALS is a distal axonopathy where early pathological changes occur at the NMJ, prior to onset of clinical symptoms and propagates towards the motor neuron cell body supporting “dying back” hypothesis. Despite several evidences, series of events triggering NMJ disassembly in ALS are still obscure. Neuromuscular junction is a specialized tripartite chemical synapse which involves a well-coordinated communication among the presynaptic motor neuron, postsynaptic skeletal muscle, and terminal Schwann cells. This review provides comprehensive insight into the role of NMJ in ALS pathogenesis. We have emphasized the molecular alterations in cellular components of NMJ leading to loss of effective neuromuscular transmission in ALS. Further, we provide a preview into research involved in exploring NMJ as potential target for designing effective therapies for ALS. 

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Acknowledgements

The authors thank Bikish Pegu for designing the illustrations and Ananya Chopra for critical reading of the manuscript.

Funding

SV is supported by the Council of Scientific and Industrial Research for SRF-NET scholarship (09/591(0150)/2018-EMR-I). AV, SK, and BS are supported by scholarship from the Indian Council of Medical Research (3/1/3/JRF-2012/HRD, BMS/Adhoc/BIOCHEM/2015–0430 and BIC/05 (09)/Indo-Russian/2016, respectively).

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Authors and Affiliations

  1. Department of Research, Sir Ganga Ram Hospital, Delhi, India

    Sagar Verma, Shiffali Khurana, Bandana Sahu, Nirmal Kumar Ganguly & Vibha Taneja

  2. Department of Biotechnology, Jamia Hamdard, Delhi, India

    Sagar Verma & Pradip Chakraborti

  3. Department of Biomedical Science, Bhaskaracharya College of Applied Sciences, University of Delhi, Delhi, India

    Shiffali Khurana

  4. Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Abhishek Vats

  5. Department of Neurophysiology, Sir Ganga Ram Hospital, Delhi, India

    Mandaville Gourie-Devi

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  1. Sagar Verma
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SV, MG, and VT: conceptualization. SV and SK: carried out literature search and wrote the original draft and illustrations. AV and BS: reviewed and edited text and figures. NG, PC, MG, and VT: critical reviewing and editing of the manuscript. All authors read and approved the final manuscript.

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Verma, S., Khurana, S., Vats, A. et al. Neuromuscular Junction Dysfunction in Amyotrophic Lateral Sclerosis. Mol Neurobiol 59, 1502–1527 (2022). https://doi.org/10.1007/s12035-021-02658-6

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