Spinal Muscular Atrophy (SMA) is a debilitating neurodegenerative disease resulting in death of the lower motor neurons, muscle atrophy, and in severe cases death. Due to mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene, levels of functional SMN protein product are decreased. While SMA was previously described as a motor neuron exclusive disorder, recent evidence suggests that many tissue and cell types throughout the body are affected. The objective of our study was to outline the effects of varying levels of SMN depletion on two genes of interest, namely Insulin-like growth factor 1 (Igf-1) and Tumor suppressor protein 53 (Trp53) in multiple tissues throughout disease course. The severe Smn2B/- and mild Smn2B/-; SMN2+/- mouse models of SMA were utilized in our studies to determine the levels of mRNA expression and subsequent protein output for these two genes. We employed RT-qPCR, western blot, and ELISA experimental methods. In Smn2B/- mice, Igf-1 mRNA was substantially decreased in symptomatic liver tissue. This was accompanied by widespread decrease in IGF-1 protein in peripheral tissues. Interestingly, this depletion effect on Igf-1 was not observed in the mild mouse model. Our analysis also showed that Trp53 mRNA was dramatically increased within tibialis anterior skeletal muscle of symptomatic Smn2B/- mice, alongside an upregulation of factors involved in p53 mediated apoptosis. Once again, this effect was not observed in the mild Smn2B/-; SMN2+/- mouse model. Overall, we have demonstrated that the extent of SMN depletion, determines whether the expression of Igf-1 and Trp53 is perturbed, suggesting that disease severity is an important factor in what pathways are affected. Finally, we show that alterations in gene expression patterns or subsequent protein levels act in a tissue-specific fashion. More investigation is encouraged to highlight IGF-1’s role as a potential SMN-independent therapeutic for SMA.

Kei Ishii, Masamichi Ishiai, Hiroko Morimoto, Mito Kanatsu-Shinohara, Ohtsura Niwa, Minoru Takata, Takashi Shinohara, The Trp53-Trp53inp1-Tnfrsf10b Pathway Regulates the Radiation Response of Mouse Spermatogonial Stem Cells, Stem Cell Reports, Volume 3, Issue 4, 14 October 2014, Pages 676-689, ISSN 2213-6711 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18685号 / 医博第3957号 / 新制||医||1007(附属図書館) / 31618 / 京都大学大学院医学研究科医学専攻 / (主査)教授 斎藤 通紀, 教授 藤田 潤, 教授 近藤 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>This research addresses low dose ionizing radiation exposure and risk. While it is well understood that high doses of radiation lead to deleterious health effects, there is controversy surrounding the definitive level of risk associated with exposure to low doses of radiation. These types of low level exposures are relevant to patients undergoing medical imaging procedures. This thesis considers the health effects associated with nuclear medicine, specifically positron emission tomography (PET), with the radiopharmaceutical 2-deoxy-2-(¹⁸F)fluoro-D-glucose(¹⁸F-FDG). These effects were studied in mice to eliminate the high degree of variability among human patients.</p> <p>The early response to various injection activities of ¹⁸F-FDG was first considered in terms of the DNA damage response in the haematopoietic cells of wild-type <em>Trp53+/+</em> mice. The late effects of PET scans with clinically relevant doses of ¹⁸F-FDG, such as carcinogenesis, were evaluated in cancer prone <em>Trp53+/-</em> mice. The role of p53 in the response to low dose radiation was also investigated to explore how short term responses correlate with p53-mediated cancer risk. This work has helped to advance the understanding of low dose radiation biology and the health risks associated with medical imaging procedures.</p> / Doctor of Philosophy (PhD)

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