PXD007178

PXD007178 is an original dataset announced via ProteomeXchange.

Title	Unravelling MYO9A pathophysiology in CMS allows the identification of a therapeutic intervention concept
Description	Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by compromised function of the neuromuscular junction (NMJ), 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 a negative regulator of RhoA and an actin-based molecular motor, loss of MYO9A was hypothesised to affect the neuronal cytoskeleton, thus leading to impaired vesicular protein transport within the neuron. MYO9A-depleted NSC-34 cells (mouse motor neuron-derived cells) were used to assess the effect on the cytoskeleton revealing altered expression of a number of cytoskeletal proteins important for neuronal cell structure and intracellular transport. Based on these findings, the effect on vesicular protein transport was determined using a vesicular recycling assay revealing impaired recycling of neuronal relevant growth factor receptor. In addition, an unbiased approach utilising proteomic profiling of control and MYO9A-depleted NSC-34 cells was utilised to identify key players of the pathophysiology. Proteomic data support a role for defective vesicular transport and identified affected proteins which are also involved in the manifestation of other neuromuscular disorders. Prompted by the clear indication of perturbed protein transportation, further proteomics-based secretomic analysis of NSC-34 cells have been performed to identify whether secretion is similarly affected. Indeed, this led to the identification of a potential therapeutic target, agrin. Zebrafish lacking MYO9A orthologues (myo9aa/ab) were treated with "Agrin Biologic", an agrin compound, and amelioration of defects in neurite extension and in movement of the zebrafish was observed. Our combined data not only allow new insights into the pathophysiology of CMS and show that loss of MYO9A affects the neuronal cytoskeleton, leading to impaired transport and vesicular recycling of proteins, but on a more general note also represent a successful biomedical approach: from the identification of the underlying pathomechanism to the definition of a therapeutic intervention concept.
HostingRepository	PRIDE
AnnounceDate	2018-10-23
AnnouncementXML	Submission_2018-10-23_15:59:49.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Vietxuan Phan
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2017-08-02 08:49:37	ID requested
⏵ 1	2018-10-23 15:59:50	announced

O'Connor E, Phan V, Cordts I, Cairns G, Hettwer S, Cox D, Lochm, ü, ller H, Roos A, MYO9A deficiency in motor neurons is associated with reduced neuromuscular agrin secretion. Hum Mol Genet, 27(8):1434-1446(2018) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: NSC34, Myo9A, LC-MSMS

Dr. rer. nat. Andreas Roos
contact affiliation	Project Leader „Tissue Proteomics“ Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V. Otto-Hahn-Str.6b 44227 Dortmund, Germany
contact email	Andreas.Roos@newcastle.ac.uk
lab head
Vietxuan Phan
contact affiliation	ISAS
contact email	vietxuan.phan@isas.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD007178
     1. Label: PRIDE project
     2. Name: Unravelling MYO9A pathophysiology in CMS allows the identification of a therapeutic intervention concept