PUBLICATION
MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion
- Authors
- O'Connor, E., Phan, V., Cordts, I., Cairns, G., Hettwer, S., Cox, D., Lochmüller, H., Roos, A.
- ID
- ZDB-PUB-180223-44
- Date
- 2018
- Source
- Human molecular genetics 27(8): 1434-1446 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Actin Cytoskeleton/metabolism
- Actin Cytoskeleton/ultrastructure
- Actins/genetics
- Actins/metabolism
- Agrin/genetics
- Agrin/metabolism*
- Amides
- Animals
- Cell Movement
- Disease Models, Animal
- Embryo, Nonmammalian
- Enzyme Inhibitors
- Gene Expression Regulation
- Humans
- Intermediate Filaments/genetics
- Intermediate Filaments/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Motor Neurons/metabolism*
- Motor Neurons/ultrastructure
- Muscle Weakness/genetics*
- Muscle Weakness/metabolism
- Muscle Weakness/pathology
- Myasthenic Syndromes, Congenital/genetics*
- Myasthenic Syndromes, Congenital/metabolism
- Myasthenic Syndromes, Congenital/pathology
- Myosins/deficiency
- Myosins/genetics*
- Nerve Growth Factor/genetics*
- Nerve Growth Factor/metabolism
- Neuromuscular Junction/metabolism*
- Neuromuscular Junction/ultrastructure
- Protein Transport
- Pyridines
- Tubulin/genetics
- Tubulin/metabolism
- Zebrafish
- rho GTP-Binding Proteins/genetics
- rho GTP-Binding Proteins/metabolism
- PubMed
- 29462312 Full text @ Hum. Mol. Genet.
Citation
O'Connor, E., Phan, V., Cordts, I., Cairns, G., Hettwer, S., Cox, D., Lochmüller, H., Roos, A. (2018) MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion. Human molecular genetics. 27(8):1434-1446.
Abstract
Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by compromised function of the neuromuscular junction, manifesting with fatigable muscle weakness. Mutations in MYO9A were previously identified as causative for CMS but the precise pathomechanism remained to be characterised. Based on the role of MYO9A as an actin-based molecular motor and as a negative regulator of RhoA, we hypothesised that loss of MYO9A may affect the neuronal cytoskeleton, leading to impaired intracellular transport. To investigate this, we used MYO9A-depleted NSC-34 cells (mouse motor neuron-derived cells), revealing altered expression of a number of cytoskeletal proteins important for neuron structure and intracellular transport. Based on these findings, the effect on protein transport was determined using a vesicular recycling assay which revealed impaired recycling of a neuronal growth factor receptor. In addition, an unbiased approach utilising proteomic profiling of the secretome revealed a key role for defective intracellular transport affecting proper protein secretion in the pathophysiology of MYO9A-related CMS. This also led to the identification of agrin as being affected by the defective transport. Zebrafish with reduced MYO9A orthologue expression were treated with an artificial agrin compound, ameliorating defects in neurite extension and improving motility. In summary, loss of MYO9A affects the neuronal cytoskeleton and leads to impaired transport of proteins, including agrin, which may provide a new and unexpected treatment option.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping