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.

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…Secondly, ubiquitous introduction of one copy of SMN2 in the Smn 2B/− mice rescued splenic and thymic phenotype 11. In a similar manner, intracerebroventricular injection of antisense oligonucleotides also abrogated the splenic defects in the Smn ∆7 spleens 10. The latter findings highlight the potential importance of autonomic nerve fibers in triggering lymphoid organ defects.…”

“…Proliferation of cells in the spleen appeared abnormal only at late stages in the Taiwanese SMA model mice, while it remained unchanged in the Smn ∆7 mice 9, 10. Investigation of cell death revealed very little change in the Taiwanese model 9.…”

“…Vasculature abnormalities were reported in other organs and could have been the initial trigger 12, 13. Immunostaining of blood vessels markers revealed very little change in the spleens of Taiwanese and Smn ∆7 mice 9, 10. However, the Smn 2B/− spleens displayed increased necrosis on gross morphological observation, which may suggest abnormal blood flow 11.…”

“…1). 9, 10, 11 The first striking abnormality in the lymphoid organs consists of a considerable reduction in spleen size, which was observed in four SMA mouse models of different severity 9, 10, 11. Interestingly, the reduction in spleen size was noted before any motor impairment, with the milder Smn 2B/− model showing the most drastic splenic atrophy 11.…”

“…Similarly, the spleen architecture was disrupted in three out of four SMA mouse models. Reduction of red pulp area, loss of clear white and red pulp borders and loss of B‐cell follicles were described 9, 10, 11. Increased fibrotic tissue and abnormal accumulation of smooth muscle cells were also noted 9, 11.…”