Dataset Information

Liver Steatosis and Mitochondrial Dysfunction in Spinal Muscular Atrophy is Survival Motor Neuron-Dependent and Hepatocyte-Intrinsic

ABSTRACT: 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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Crystal Yeo Jing Jing

PROVIDER: PXD045401 | JPOST Repository | Thu May 09 00:00:00 BST 2024

REPOSITORIES: jPOST

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Dataset's files

Source:

			Action	DRS
	20190611_Human_UniProt.fasta	Fasta
	20220611_TY_Damien_Pellet_TMT16_Set1.msf	Msf
	20220611_TY_Damien_Pellet_TMT16_Set1.pdResult	Other
	20220611_TY_Damien_Pellet_TMT16_Set1_F1.raw	Raw
	20220611_TY_Damien_Pellet_TMT16_Set1_F2.raw	Raw

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Publications

Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy.

Leow Damien Meng-Kiat DM Ng Yang Kai YK Wang Loo Chien LC Koh Hiromi Wl HW Zhao Tianyun T Khong Zi Jian ZJ Tabaglio Tommaso T Narayanan Gunaseelan G Giadone Richard M RM Sobota Radoslaw M RM Ng Shi-Yan SY Teo Adrian Kee Keong AKK Parson Simon H SH Rubin Lee L LL Ong Wei-Yi WY Darras Basil T BT Yeo Crystal Jj CJ

The Journal of clinical investigation 20240509 12

Spinal muscular atrophy (SMA) is typically characterized as a motor neuron disease, but extraneuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extraneuronal phenotypes were previously underappreciated, as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to ...[more]

PMID: 38722695

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