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

Autor:	Leow DM; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Ng YK; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Wang LC; Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore., Koh HW; Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore., Zhao T; Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore., Khong ZJ; Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore., Tabaglio T; Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore., Narayanan G; Duke-NUS Medical School, Singapore, Singapore., Giadone RM; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America., Sobota RM; Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore., Ng SY; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Teo AK; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Parson SH; Institute of Education in Healthcare and Medical Sciences, School of Medici, University of Aberdeen, Aberdeen, United Kingdom., Rubin LL; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States of America., Ong WY; Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Darras BT; Department of Neurology, Boston Children's Hospital, Boston, United States of America., Yeo CJ; Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 May 09. Date of Electronic Publication: 2024 May 09.
DOI:	10.1172/JCI173702
Abstrakt:	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.
Databáze:	MEDLINE
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