PXD045401-1

PXD045401 is an original dataset announced via ProteomeXchange.

Title	Liver Steatosis and Mitochondrial Dysfunction in Spinal Muscular Atrophy is Survival Motor Neuron-Dependent and Hepatocyte-Intrinsic
Description	Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extra-neuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons which increase patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in animal models of SMA, but generalizability to patients and whether this is due to hepatocyte-intrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyte-intrinsic, this provides proof of concept that SMN repleting therapies must target extra-neuronal tissues as well as motor neurons for optimal patient outcome. Here we show that fatty liver is present in SMA and that SMA patient-specific iHeps are susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirm that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism dysfunctions. These pathologies require monitoring and indicate the need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.
HostingRepository	jPOST
AnnounceDate	2024-05-09
AnnouncementXML	Submission_2024-05-26_20:32:36.833.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Radoslaw Sobota
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; L-methionine sulfoxide; alpha-amino acetylated residue; deamidated L-glutamine; deamidated L-asparagine
Instrument	instrument

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-14 20:05:20	ID requested
⏵ 1	2024-05-26 20:32:37	announced

Leow DM, Ng YK, Wang LC, Koh HW, Zhao T, Khong ZJ, Tabaglio T, Narayanan G, Giadone RM, Sobota RM, Ng SY, Teo AK, Parson SH, Rubin LL, Ong WY, Darras BT, Yeo CJ, Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy. J Clin Invest, 134(12):(2024) [pubmed]

submitter keyword: induced hepatocellular carcinoma, spinal muscular atrophy

Crystal Yeo Jing Jing
lab head
Radoslaw Sobota
contact affiliation	IMCB A-STAR Singapore
dataset submitter

jPOST dataset URI

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