Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes
Abstract
:1. Introduction
2. Methodology
3. Animal Models Used in the Study of CMS-Associated Proteins
3.1. Post-Synaptic
3.1.1. AChR Deficiency
3.1.2. AChR Kinetic Mutations
3.1.3. MuSK/LRP4
3.1.4. Rapsyn
3.1.5. DOK7
3.2. Synaptic
3.2.1. ColQ
3.2.2. Agrin
3.2.3. The Extracellular Matrix (ECM)
3.3. Pre-Synaptic
4. Animal Models in Myasthenia Gravis
5. Conclusions
Acknowledgements
Conflicts of Interest
Abbreviations
AAV | Adeno-Associated Virus |
ACh | Acetylcholine |
AChE | Acetylcholine Esterase |
AChR | Acetylcholine Receptor |
ChAT | Choline Acetyltransferase |
CMAP | Compound Muscle Action Potential |
CMS | Congenital Myasthenic Syndrome |
Col13A1 | Collagen, Type XIII, α-1 |
Col-Q | Collagen Like Tail Subunit of Asymmetric Acetylcholinesterase |
DOK7 | Downstream of Tyrosine Kinase-7 |
EPC | Endplate Current |
EPP | Endplate Potential |
LRP4 | Low Density Lipoprotein Receptor (LDLR)-related protein 4 |
mEPP | Miniature Endplate Potential |
MuSK | Muscle-Specific Kinase |
NMJ | Neuromuscular Junction |
P | Postnatal day |
QC | Quantal Content |
Rapsyn | Receptor-Associated Protein of the Synapse |
SCCMS | Slow Channel Congenital Myasthenic Syndrome |
SCL5A7 | Solute Carrier Family 5 (Choline Transporter), Member 7 |
SLC18A3 | Solute Carrier Family 18 (Vesicular Acetylcholine), Member 3 |
SNAP25 | Synaptosomal-Associated Protein, 25-KD |
SYT2 | Synaptotagmin 2 |
VAMP1 | Vesicle-Associated Membrane Protein 1 |
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CMS Disorder | CMS Subtype | Gene | Description | References |
---|---|---|---|---|
AChR-Deficiency | CMS4C | CHRNE, CHRNG | Expression of γ-AChR in ε-AChR knockout background generates weak mice with reduced endplate depolarisation but normal lifespan. | [3] |
AChR-Slow channel kinetic | CMS4A, CMS1A, CMS3A | CHRNE, CHRNA1, CHRND | Expression of slow channel kinetic mutant AChR replicates prolongation of AChR current, muscle weakness, calcium overload and response to treatment. | [4,5,6,7,8,9,10,11,12] |
MuSK | CMS9 | MUSK | Hemizygous expression of V789M mutant in knockout background generates overtly weak mouse with defects of NMJ structure and neurotransmission. | [13] |
Rapsyn | CMS11 | RAPSN | Mutation within RING-domain of rapsyn inhibits E3-ligase activity, disrupts AChR cluster formation, motor nerve targeting and is perinatally lethal. | [14] |
DOK7 | CMS10 | DOK7 | Duplication mutation (c.1124_1127dupTGCC) disrupts NMJ formation and is perinatally lethal.Overexpression of DOK7 rescues phenotype. | [15] |
Agrin | CMS8 | AGRN | Chemically generated missense mutation causes NMJ degradation with decreased AChR density and reduced lifespan. | [16] |
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Webster, R.G. Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes. Int. J. Mol. Sci. 2018, 19, 1326. https://doi.org/10.3390/ijms19051326
Webster RG. Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes. International Journal of Molecular Sciences. 2018; 19(5):1326. https://doi.org/10.3390/ijms19051326
Chicago/Turabian StyleWebster, Richard G. 2018. "Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes" International Journal of Molecular Sciences 19, no. 5: 1326. https://doi.org/10.3390/ijms19051326