title: SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease that is the leading genetic cause of infantile death. It is caused by a severe deficiency of the ubiquitously expressed Survival Motor Neuron (SMN) protein. SMA is characterized by α-lower motor neuron loss and muscle atrophy, however, there is a growing list of tissues impacted by a SMN deficiency beyond motor neurons. The non-neuronal defects are observed in the most severe Type I SMA patients and most of the widely used SMA mouse models, however, as effective therapeutics are developed, it is unclear whether additional symptoms will be uncovered in longer lived patients. Recently, the immune system and inflammation has been identified as a contributor to neurodegenerative diseases such as ALS. To determine whether the immune system is comprised in SMA, we analyzed the spleen and immunological components in SMA mice. In this report, we identify: a significant reduction in spleen size in multiple SMA mouse models and a pathological reduction in red pulp and extramedullary hematopoiesis. Additionally, red pulp macrophages, a discrete subset of yolk sac-derived macrophages, were found to be altered in SMA spleens even in pre-symptomatic post-natal day 2 animals. These cells, which are involved in iron metabolism and the phagocytosis of erythrocytes and blood-borne pathogens are significantly reduced prior to the development of the neurodegenerative hallmarks of SMA, implying a differential role of SMN in myeloid cell ontogeny. Collectively, these results demonstrate that SMN deficiency impacts spleen development and suggests a potential role for immunological development in SMA.
authors.affiliation: Molecular Pathogeneses and Therapeutics Program.|Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Khairallah
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Astroski
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Custer
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Androphy
authors.affiliation: MU Mutant Mouse Resource and Research Center.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Franklin
authors.affiliation: Molecular Pathogeneses and Therapeutics Program.|Bond Life Sciences Center, University of Missouri, Columbia, MO, USA.|Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lorson
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics* / Q000276:immunology; D004912:Erythrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006411:Hematopoiesis, Extramedullary; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007501:Iron / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009046:Motor Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000254:growth & development / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D007501:Iron