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Title: Organ developmental and maturational defects in Spinal Muscular Atrophy
Author: Thomson, Alison Kathryn
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2016
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Spinal Muscular Atrophy (SMA), traditionally described as a predominantly childhood form of motor neuron disease, is a leading genetic cause of infant mortality. Although motor neurons are undoubtedly the primary affected cell type, SMA is now widely recognised as a multisystem disorder, where a variety of organs and systems in the body are also affected. Vascular perfusion abnormalities have previously been reported in both patients and mouse models of SMA, however it remains unclear whether these defects are secondary to the motor neuron pathology for which this disease is known. Through analysis of the 'Taiwanese' murine model of severe SMA (Smn-/-;SMN2tg/0, Smn-/+) we report significant vascular defects in the retinas of SMA mice, a tissue devoid of motor neurons, thus providing strong evidence that these vascular defects are independent of motor neuron pathologies. We show that restoration of Smn levels by antisense oligonucleotide treatment at birth significantly ameliorates retinal vascular defects. Next, we report defects in the neural retina, with a significant decrease in key neural cells in SMA mice. A similar vascular pathology was expected in the spleen of SMA mice given that the spleen is small and pale in appearance; however, the density of the intrinsic vasculature remained unchanged. We report that the spleen is disproportionately small in SMA mice, correlated to low levels of cell proliferation, increased cell death, and multiple lacunae. The SMA spleen lacks its distinctive red appearance and presents with a degenerated capsule and a disorganized fibrotic architecture. Histologically distinct white pulp fails to form and this is reflected in an almost complete absence of B lymphocytes necessary for normal immune function. Taken together, these results highlight both the vascular and immune systems as key targets of SMA pathology that should be considered during treatment of this disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Spinal muscular atrophy ; Organs (Anatomy) ; Abnormalities ; Human