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- Title
MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion.
- Authors
O'Connor, Emily; Phan, Vietxuan; Cordts, Isabell; Cairns, George; Hettwer, Stefan; Cox, Daniel; Lochmüller1, Hanns; Roos, Andreas
- Abstract
Congenitalmyasthenic syndromes (CMS) are a group of rare, inherited disorders characterized 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 characterized. On the basis of the role ofMYO9A as an actinbasedmolecularmotor and as a negative regulator of RhoA, we hypothesized that loss ofMYO9Amay affect the neuronal cytoskeleton, leading to impaired intracellular transport. To investigate this, we usedMYO9A-depleted NSC-34 cells (mousemotor neuron-derived cells), revealing altered expression of a number of cytoskeletal proteins important for neuron structure and intracellular transport. On the basis of 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 utilizing proteomic profiling of the secretome revealed a key role for defective intracellular transport affecting proper protein secretion in the pathophysiology ofMYO9A-related CMS. This also led to the identification of agrin as being affected by the defective transport. Zebrafish with reducedMYO9A orthologue expression were treated with an artificial agrin compound, ameliorating defects in neurite extension and improvingmotility. In summary, loss ofMYO9A affects the neuronal cytoskeleton and leads to impaired transport of proteins, including agrin, whichmay provide a new and unexpected treatment option.
- Publication
Human Molecular Genetics, 2018, Vol 27, Issue 8, p1434
- ISSN
0964-6906
- Publication type
Article
- DOI
10.1093/hmg/ddy054