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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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 Kk AK 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

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 increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to ...[more]

PMID: 38722695

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Dataset Information

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

Publications

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

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