
Liver-specific depletion of the survival motor neuron (SMN) protein leads to mild liver steatosis and disrupts pancreatic function, but does not induce motor neuron degeneration or neuromuscular pathology typically observed in spinal muscular atrophy (SMA).


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Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder stemming from deletions or mutations in the Survival Motor Neuron 1 ( SMN1 ) gene, leading to decreased levels of SMN protein, and subsequent motor neuron death and muscle atrophy. While traditionally viewed as a disorder predominantly affecting motor neurons, recent research suggests the involvement of various peripheral organs in SMA pathology. Notably, the liver has emerged as a significant focus due to the observed fatty liver phenotype and dysfunction in both SMA mouse models and SMA patients. Despite these findings, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this knowledge gap, we developed a mouse model with a liver-specific depletion of SMN by utilizing an Alb-Cre transgene together with one Smn2B allele and one Smn exon 7 allele flanked by loxP sites. We evaluated phenotypic changes in these mice at postnatal day 19 (P19), a time when the severe model of SMA, the Smn2B/- mice, typically exhibit many symptoms of the disease. Our findings indicate that liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in the Smn 2B/- mouse at P19. However, mild liver steatosis was observed at this time point, although no changes in liver function were detected. Notably, pancreatic alterations resembled that of Smn2B/- mice, with a decrease in insulin producing alpha-cells and an increase in glucagon producing beta-cells, accompanied with a reduction in blood glucose levels. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA, adding a nuanced layer to our understanding of the disease’s complexities.

### Competing Interest Statement

The authors have declared no competing interest.

Impact of liver specific survival motor neuron (SMN) depletion on peripheral and central nervous system tissue pathology

liver-specific-depletion-of-survival-motor-neuron-smn-protein-does-not-induce-motor-neuron-pathology-but-alters-pancreatic-function-in-mice


Liver-Specific Depletion of Survival Motor Neuron (SMN) Protein Does Not Induce Motor Neuron Pathology but Alters Pancreatic Function in Mice
