PMID- 35468848
OWN - NLM
STAT- MEDLINE
DCOM- 20220427
LR  - 20220716
IS  - 2051-5960 (Electronic)
IS  - 2051-5960 (Linking)
VI  - 10
IP  - 1
DP  - 2022 Apr 25
TI  - Impaired signaling for neuromuscular synaptic maintenance is a feature of Motor 
      Neuron Disease.
PG  - 61
LID - 10.1186/s40478-022-01360-5 [doi]
LID - 61
AB  - 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.
CI  - (c) 2022. The Author(s).
FAU - Ding, Qiao
AU  - Ding Q
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
FAU - Kesavan, Kaamini
AU  - Kesavan K
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
FAU - Lee, Kah Meng
AU  - Lee KM
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
FAU - Wimberger, Elyse
AU  - Wimberger E
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
FAU - Robertson, Thomas
AU  - Robertson T
AD  - Pathology Queensland, Faculty of Medicine, Royal Brisbane and Women's Hospital, 
      Herston, QLD, 4006, Australia.
FAU - Gill, Melinder
AU  - Gill M
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
FAU - Power, Dominique
AU  - Power D
AD  - Australian Institute for Bioengineering and Nanotechnology, The University of 
      Queensland, St. Lucia, QLD, 4072, Australia.
FAU - Chang, Jeryn
AU  - Chang J
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
AD  - Australian Institute for Bioengineering and Nanotechnology, The University of 
      Queensland, St. Lucia, QLD, 4072, Australia.
FAU - Fard, Atefeh T
AU  - Fard AT
AD  - Australian Institute for Bioengineering and Nanotechnology, The University of 
      Queensland, St. Lucia, QLD, 4072, Australia.
FAU - Mar, Jessica C
AU  - Mar JC
AD  - Australian Institute for Bioengineering and Nanotechnology, The University of 
      Queensland, St. Lucia, QLD, 4072, Australia.
FAU - Henderson, Robert D
AU  - Henderson RD
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, 4006, Herston, QLD, 
      Australia.
AD  - University of Queensland Centre for Clinical Research, The University of 
      Queensland, Herston, QLD, 4006, Australia.
FAU - Heggie, Susan
AU  - Heggie S
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, 4006, Herston, QLD, 
      Australia.
FAU - McCombe, Pamela A
AU  - McCombe PA
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, 4006, Herston, QLD, 
      Australia.
AD  - University of Queensland Centre for Clinical Research, The University of 
      Queensland, Herston, QLD, 4006, Australia.
FAU - Jeffree, Rosalind L
AU  - Jeffree RL
AD  - Department of Neurosurgery, Royal Brisbane and Women's Hospital, Herston, QLD, 
      4006, Australia.
FAU - Colditz, Michael J
AU  - Colditz MJ
AD  - Department of Neurosurgery, Royal Brisbane and Women's Hospital, Herston, QLD, 
      4006, Australia.
FAU - Hilliard, Massimo A
AU  - Hilliard MA
AD  - Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The 
      University of Queensland, St. Lucia, QLD, 4072, Australia.
FAU - Ng, Dominic C H
AU  - Ng DCH
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
FAU - Steyn, Frederik J
AU  - Steyn FJ
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, 4006, Herston, QLD, 
      Australia.
AD  - University of Queensland Centre for Clinical Research, The University of 
      Queensland, Herston, QLD, 4006, Australia.
FAU - Phillips, William D
AU  - Phillips WD
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia.
FAU - Wolvetang, Ernst J
AU  - Wolvetang EJ
AD  - Australian Institute for Bioengineering and Nanotechnology, The University of 
      Queensland, St. Lucia, QLD, 4072, Australia.
FAU - Ngo, Shyuan T
AU  - Ngo ST
AUID- ORCID: 0000-0002-1388-2108
AD  - Australian Institute for Bioengineering and Nanotechnology, The University of 
      Queensland, St. Lucia, QLD, 4072, Australia. s.ngo@uq.edu.au.
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, 4006, Herston, QLD, 
      Australia. s.ngo@uq.edu.au.
AD  - University of Queensland Centre for Clinical Research, The University of 
      Queensland, Herston, QLD, 4006, Australia. s.ngo@uq.edu.au.
FAU - Noakes, Peter G
AU  - Noakes PG
AUID- ORCID: 0000-0001-9821-8478
AD  - School of Biomedical Sciences, The University of Queensland, St. Lucia, QLD, 
      4072, Australia. p.noakes@uq.edu.au.
AD  - Department of Neurology, Royal Brisbane and Women's Hospital, 4006, Herston, QLD, 
      Australia. p.noakes@uq.edu.au.
AD  - Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The 
      University of Queensland, St. Lucia, QLD, 4072, Australia. p.noakes@uq.edu.au.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220425
PL  - England
TA  - Acta Neuropathol Commun
JT  - Acta neuropathologica communications
JID - 101610673
RN  - 0 (Agrin)
RN  - 0 (LDL-Receptor Related Proteins)
RN  - 0 (Receptors, Cholinergic)
SB  - IM
MH  - *Agrin/metabolism
MH  - Humans
MH  - LDL-Receptor Related Proteins/metabolism
MH  - *Motor Neuron Disease
MH  - Receptors, Cholinergic/metabolism
MH  - Signal Transduction
PMC - PMC9040261
OTO - NOTNLM
OT  - ALS
OT  - Acetylcholine receptors
OT  - Agrin
OT  - Amyotrophic Lateral Sclerosis
OT  - Motor neurons
OT  - MuSK
OT  - Neuromuscular junction
COIS- All authors declare no competing interests.
EDAT- 2022/04/27 06:00
MHDA- 2022/04/28 06:00
PMCR- 2022/04/25
CRDT- 2022/04/26 05:11
PHST- 2022/04/06 00:00 [received]
PHST- 2022/04/06 00:00 [accepted]
PHST- 2022/04/26 05:11 [entrez]
PHST- 2022/04/27 06:00 [pubmed]
PHST- 2022/04/28 06:00 [medline]
PHST- 2022/04/25 00:00 [pmc-release]
AID - 10.1186/s40478-022-01360-5 [pii]
AID - 1360 [pii]
AID - 10.1186/s40478-022-01360-5 [doi]
PST - epublish
SO  - Acta Neuropathol Commun. 2022 Apr 25;10(1):61. doi: 10.1186/s40478-022-01360-5.