PMID- 34360794
OWN - NLM
STAT- MEDLINE
DCOM- 20210908
LR  - 20210908
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 15
DP  - 2021 Jul 27
TI  - Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the 
      Delta7 Mouse Model of Spinal Muscular Atrophy (SMA).
LID - 10.3390/ijms22158015 [doi]
LID - 8015
AB  - Spinal muscular atrophy (SMA) is a motor neuron disease caused by insufficient 
      levels of the survival motor neuron (SMN) protein. One of the most prominent 
      pathological characteristics of SMA involves defects of the neuromuscular 
      junction (NMJ), such as denervation and reduced clustering of acetylcholine 
      receptors (AChRs). Recent studies suggest that upregulation of agrin, a crucial 
      NMJ organizer promoting AChR clustering, can improve NMJ innervation and reduce 
      muscle atrophy in the delta7 mouse model of SMA. To test whether the 
      muscle-specific kinase (MuSK), part of the agrin receptor complex, also plays a 
      beneficial role in SMA, we treated the delta7 SMA mice with an agonist antibody 
      to MuSK. MuSK agonist antibody #13, which binds to the NMJ, significantly 
      improved innervation and synaptic efficacy in denervation-vulnerable muscles. 
      MuSK agonist antibody #13 also significantly increased the muscle cross-sectional 
      area and myofiber numbers in these denervation-vulnerable muscles but not in 
      denervation-resistant muscles. Although MuSK agonist antibody #13 did not affect 
      the body weight, our study suggests that preservation of NMJ innervation by the 
      activation of MuSK may serve as a complementary therapy to SMN-enhancing drugs to 
      maximize the therapeutic effectiveness for all types of SMA patients.
FAU - Feng, Zhihua
AU  - Feng Z
AD  - Section of Neurobiology, Department of Biological Sciences, University of 
      Southern California, Los Angeles, CA 90089, USA.
FAU - Lam, Steven
AU  - Lam S
AD  - Section of Neurobiology, Department of Biological Sciences, University of 
      Southern California, Los Angeles, CA 90089, USA.
FAU - Tenn, Elena-Marie Sandino
AU  - Tenn ES
AD  - Section of Neurobiology, Department of Biological Sciences, University of 
      Southern California, Los Angeles, CA 90089, USA.
FAU - Ghosh, Arundhati Sengupta
AU  - Ghosh AS
AD  - Department of Neuroscience, Genentech, South San Francisco, CA 94080, USA.
FAU - Cantor, Sarah
AU  - Cantor S
AD  - Department of Neuroscience, Skirball Institute of Biomolecular Medicine, New York 
      University, New York City, NY 10016, USA.
FAU - Zhang, Wei
AU  - Zhang W
AUID- ORCID: 0000-0001-7601-7034
AD  - Department of Neuroscience, Skirball Institute of Biomolecular Medicine, New York 
      University, New York City, NY 10016, USA.
FAU - Yen, Pei-Fen
AU  - Yen PF
AD  - Section of Neurobiology, Department of Biological Sciences, University of 
      Southern California, Los Angeles, CA 90089, USA.
FAU - Chen, Karen S
AU  - Chen KS
AD  - Spinal Muscular Atrophy Foundation, P.O. Box 9214, Jackson, WY 83002, USA.
FAU - Burden, Steven
AU  - Burden S
AD  - Department of Neuroscience, Skirball Institute of Biomolecular Medicine, New York 
      University, New York City, NY 10016, USA.
FAU - Paushkin, Sergey
AU  - Paushkin S
AD  - Spinal Muscular Atrophy Foundation, P.O. Box 9214, Jackson, WY 83002, USA.
FAU - Ayalon, Gai
AU  - Ayalon G
AUID- ORCID: 0000-0002-0872-9168
AD  - Ultragenyx Pharmaceutical, Novato, CA 94949, USA.
FAU - Ko, Chien-Ping
AU  - Ko CP
AUID- ORCID: 0000-0002-3365-0005
AD  - Section of Neurobiology, Department of Biological Sciences, University of 
      Southern California, Los Angeles, CA 90089, USA.
LA  - eng
GR  - N/A/Spinal Muscular Atrophy Foundation/
PT  - Journal Article
DEP - 20210727
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Smn1 protein, mouse)
RN  - 0 (Survival of Motor Neuron 1 Protein)
RN  - EC 2.7.10.1 (MuSK protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Animals
MH  - Disease Models, Animal
MH  - Enzyme Activation
MH  - Mice
MH  - Mice, Transgenic
MH  - Motor Neurons/*enzymology/pathology
MH  - Muscular Atrophy, Spinal/*enzymology/genetics/pathology
MH  - Neuromuscular Junction/*enzymology/genetics/pathology
MH  - Receptor Protein-Tyrosine Kinases/genetics/*metabolism
MH  - Survival of Motor Neuron 1 Protein/genetics/metabolism
PMC - PMC8348537
OTO - NOTNLM
OT  - denervation
OT  - innervation
OT  - muscle-specific kinase (MuSK)
OT  - neuromuscular junction
OT  - skeletal muscle
OT  - spinal muscular atrophy
COIS- A.S.G. is financially compensated as employees of Genentech. G.A. is an employee 
      of Ultragenyx Pharmaceutical. The funders (S.P. and K.S.C.) had no role other 
      than what was listed above in the Author Contribution section. All other authors 
      declare no conflict of interest.
EDAT- 2021/08/08 06:00
MHDA- 2021/09/09 06:00
PMCR- 2021/07/27
CRDT- 2021/08/07 01:07
PHST- 2021/05/31 00:00 [received]
PHST- 2021/07/22 00:00 [revised]
PHST- 2021/07/23 00:00 [accepted]
PHST- 2021/08/07 01:07 [entrez]
PHST- 2021/08/08 06:00 [pubmed]
PHST- 2021/09/09 06:00 [medline]
PHST- 2021/07/27 00:00 [pmc-release]
AID - ijms22158015 [pii]
AID - ijms-22-08015 [pii]
AID - 10.3390/ijms22158015 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 Jul 27;22(15):8015. doi: 10.3390/ijms22158015.