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ResearchIn-Press PreviewMetabolismNeuroscience Open Access | 10.1172/JCI173702
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
Find articles by Wang, L. in: JCI | PubMed | Google Scholar
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
Find articles by Koh, H. in: JCI | PubMed | Google Scholar
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
Find articles by Zhao, T. in: JCI | PubMed | Google Scholar
1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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1Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
3Duke-NUS Medical School, Singapore, Singapore
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America
5Yong Loo Lin School of Medicine, National University of Singapore, Proteos, Singapore
6Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom
7Department of Stem Cell and Regenerative Biology, Harvard University, Boston, United States of America
8Department of Neurology, Boston Children's Hospital, Boston, United States of America
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Published May 9, 2024 - More info
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.