Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease

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Abstract

A central event in the pathogenesis of motor neuron disease (MND) is the loss of neuromuscular junctions (NMJs), yet the mechanisms that lead to this event in MND remain to be fully elucidated. Maintenance of the NMJ relies upon neural agrin ( n-agrin) which, when released from the nerve terminal, activates the postsynaptic Muscle Specific Kinase (MuSK) signaling complex to stabilize clusters of acetylcholine receptors. Here, we report that muscle from MND patients has an increased proportion of slow fibers and muscle fibers with smaller diameter. Muscle cells cultured from MND biopsies failed to form large clusters of acetylcholine receptors in response to either non-MND human motor axons or n-agrin. Furthermore, levels of expression of MuSK, and MuSK-complex components: LRP4, Caveolin-3, and Dok7 differed between muscle cells cultured from MND patients compared to those from non-MND controls. To our knowledge, this is the first time a fault in the n-agrin-LRP4-MuSK signaling pathway has been identified in muscle from MND patients. Our results highlight the n-agrin-LRP4-MuSK signaling pathway as a potential therapeutic target to prolong muscle function in MND.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40478-022-01360-5.

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Summary Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultra-sensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies, and mice in vivo. In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5 - 40 micrometers long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales.

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Author and article information

Contributors

Shyuan T. Ngo:

ORCID: http://orcid.org/0000-0002-1388-2108

s.ngo@uq.edu.au

Peter G. Noakes:

ORCID: http://orcid.org/0000-0001-9821-8478

p.noakes@uq.edu.au

Journal

Journal ID (nlm-ta): Acta Neuropathol Commun

Journal ID (iso-abbrev): Acta Neuropathol Commun

Title: Acta Neuropathologica Communications

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-5960

Publication date (Electronic): 25 April 2022

Publication date PMC-release: 25 April 2022

Publication date Collection: 2022

Volume: 10

Electronic Location Identifier: 61

Affiliations

[1 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, School of Biomedical Sciences, , The University of Queensland, ; St. Lucia, QLD 4072 Australia

[2 ]GRID grid.416100.2, ISNI 0000 0001 0688 4634, Pathology Queensland, Faculty of Medicine, , Royal Brisbane and Women’s Hospital, ; Herston, QLD 4006 Australia

[3 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Australian Institute for Bioengineering and Nanotechnology, , The University of Queensland, ; St. Lucia, QLD 4072 Australia

[4 ]GRID grid.416100.2, ISNI 0000 0001 0688 4634, Department of Neurology, , Royal Brisbane and Women’s Hospital, ; 4006, Herston, QLD Australia

[5 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, University of Queensland Centre for Clinical Research, , The University of Queensland, ; Herston, QLD 4006 Australia

[6 ]GRID grid.416100.2, ISNI 0000 0001 0688 4634, Department of Neurosurgery, , Royal Brisbane and Women’s Hospital, ; Herston, QLD 4006 Australia

[7 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, , The University of Queensland, ; St. Lucia, QLD 4072 Australia

Author information

Shyuan T. Ngo http://orcid.org/0000-0002-1388-2108

Peter G. Noakes http://orcid.org/0000-0001-9821-8478

Article

Publisher ID: 1360

DOI: 10.1186/s40478-022-01360-5

PMC ID: 9040261

PubMed ID: 35468848

SO-VID: 77c7049e-75d9-4be5-8a01-9561875c26c4

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 6 April 2022

Date accepted : 6 April 2022

Funding

Funded by: National Health & Medical Research Council Australia

Award ID: 1188169

Award ID: 1101085

Award Recipient : Frederik J. Steyn William D. Phillips Shyuan T. Ngo Peter G. Noakes

Funded by: MNDRIA

Award ID: GIV 1842

Award Recipient : Peter G. Noakes

Funded by: MNDRIA

Funded by: MND & Me Foundation Fellowship

Funded by: FundRef http://dx.doi.org/10.13039/100014012, FightMND;

Award ID: Fellowship

Award Recipient : Shyuan T. Ngo

Funded by: FundRef http://dx.doi.org/10.13039/501100004543, China Scholarship Council;

Custom metadata

Keywords: amyotrophic lateral sclerosis,als,neuromuscular junction,musk,agrin,motor neurons,acetylcholine receptors

Data availability:

Keywords: amyotrophic lateral sclerosis, als, neuromuscular junction, musk, agrin, motor neurons, acetylcholine receptors

Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor Neuron Disease

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Neuronal Signaling

Most cited references 84

Fiji: an open-source platform for biological-image analysis.

Comprehensive Integration of Single-Cell Data

Ultra-sensitive fluorescent proteins for imaging neuronal activity

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