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

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 usual...

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Published in:	The Journal of clinical investigation Vol. 134; no. 12
Main Authors:	Leow, Damien Meng-Kiat, Ng, Yang Kai, Wang, Loo Chien, Koh, Hiromi Wl, Zhao, Tianyun, Khong, Zi Jian, Tabaglio, Tommaso, Narayanan, Gunaseelan, Giadone, Richard M, Sobota, Radoslaw M, Ng, Shi-Yan, Teo, Adrian Kk, Parson, Simon H, Rubin, Lee L, Ong, Wei-Yi, Darras, Basil T, Yeo, Crystal Jj
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 15-06-2024
Subjects:	Complications and side effects Development and progression Fatty liver Genes Health aspects Liver Liver cells Liver diseases Medical research Medicine, Experimental Metabolic diseases Muscles Neurons Phenotype Physiological aspects Risk factors Spinal muscular atrophy Stem cells Singapore Neuromuscular disease Metabolism Neuroscience
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Summary:	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 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 extra-neuronal tissues and motor neurons for optimal patient outcome. Here we showed that fatty liver is present in SMA and that SMA patient-specific iHeps 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 need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: DMKL and YKN are co–first authors.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI173702