Journal Article

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

Wang, Loo Chien, Giadone, Richard M., Sobota, Radoslaw M., Ong, Wei-Yi, Zhao, Tianyun, Ng, Yang Kai, Khong, Zi Jian, Leow, Damien Meng-Kiat, Rubin, Lee L., Narayanan, Gunaseelan, Teo, Adrian Kee Keong, Yeo, Crystal J.J., Koh, Hiromi W.L., Parson, Simon H., Tabaglio, Tommaso, Ng, Shi-Yan, Darras, Basil T.

2024

Overview

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 new treatment-modified phenotypes. Fatty liver is seen in SMA animal models, 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 suggests SMN-repleting therapies must target extraneuronal tissues and motor neurons for optimal patient outcome. Here, we showed that fatty liver is present in SMA patients and that SMA patient-specific induced pluripotent stem cell-derived hepatocyte-like cells were susceptible to steatosis. Using proteomics, functional studies, and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate the need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Complications and side effects / Development and progression / Fatty liver / Fatty Liver - genetics / Fatty Liver - metabolism / Fatty Liver - pathology / Female / Genes / Health aspects / Hepatocytes - metabolism / Hepatocytes - pathology / Humans / Induced Pluripotent Stem Cells - metabolism / Induced Pluripotent Stem Cells - pathology / Liver / Liver cells / Liver diseases / Male / Medical research / Medicine, Experimental / Metabolic diseases / Metabolism / Mice / Muscles / Muscular Atrophy, Spinal - complications / Muscular Atrophy, Spinal - genetics / Muscular Atrophy, Spinal - metabolism / Muscular Atrophy, Spinal - pathology / Neurons / Neuroscience / Phenotype / Physiological aspects / Risk factors / Spinal muscular atrophy / Stem cells / Survival of Motor Neuron 1 Protein - genetics / Survival of Motor Neuron 1 Protein - metabolism