The master regulator of metabolism and growth, mechanistic target of rapamycin complex 1 (mTORC1), is responsible for maintaining metabolic homeostasis by sensing nutrient and energy levels within the cell to promote or inhibit translation and autophagy accordingly. In the childhood neurodevelopmental disorder Mucolipidosis type IV (MLIV), mTORC1 activity is decreased. The underlying mechanism for reduced mTORC1 signaling in MLIV is poorly understood. The gene encoding ganglioside-induced differentiation associated protein 1 (GDAP1) is transcriptionally upregulated in MLIV. This project investigated the involvement of GDAP1 in MLIV disease pathology. Using the UAS/GAL4 system in an established MLIV Drosophila model, we knocked down expression of GDAP1. To determine the effect on mTORC1 activity, we measured phosphorylation levels of the mTORC1 downstream target S6 kinase (S6K) and quantified changes in synaptic growth at the larval neuromuscular junction (NMJ), which is a cell biological readout for mTORC1 activity. We found that knocking down GDAP1 expression can partially suppress the decreased phosphorylated S6K levels and rescue the reduced NMJ synaptic growth that occurs in MLIV Drosophila larvae. These results indicate that GDAP1 plays a role upstream of mTORC1 to affect signaling in MLIV cells. With this knowledge, we draw closer to understanding the dysregulation of mTORC1 signaling that occurs in MLIV patients and gain insight into an incompletely understood mechanism for regulating metabolism.
","abstract_html":"<p>The master regulator of metabolism and growth, mechanistic target of rapamycin complex 1 (mTORC1), is responsible for maintaining metabolic homeostasis by sensing nutrient and energy levels within the cell to promote or inhibit translation and autophagy accordingly. In the childhood neurodevelopmental disorder Mucolipidosis type IV (MLIV), mTORC1 activity is decreased. The underlying mechanism for reduced mTORC1 signaling in MLIV is poorly understood. The gene encoding ganglioside-induced differentiation associated protein 1 (<em>GDAP1</em>) is transcriptionally upregulated in MLIV. This project investigated the involvement of GDAP1 in MLIV disease pathology. Using the <em>UAS/GAL4</em> system in an established MLIV <em>Drosophila</em> model, we knocked down expression of <em>GDAP1</em>. To determine the effect on mTORC1 activity, we measured phosphorylation levels of the mTORC1 downstream target S6 kinase (S6K) and quantified changes in synaptic growth at the larval neuromuscular junction (NMJ), which is a cell biological readout for mTORC1 activity. We found that knocking down <em>GDAP1</em> expression can partially suppress the decreased phosphorylated S6K levels and rescue the reduced NMJ synaptic growth that occurs in MLIV<em> Drosophila</em> larvae. These results indicate that GDAP1 plays a role upstream of mTORC1 to affect signaling in MLIV cells. With this knowledge, we draw closer to understanding the dysregulation of mTORC1 signaling that occurs in MLIV patients and gain insight into an incompletely understood mechanism for regulating metabolism.</p>","abstract_has_math":false,"creators":["Clemons, Kristen","https://orcid.org/0000-0001-9449-896X
"],"institution":null,"degree_name":"Masters of Science (MS)","degree_level":"Thesis (MS)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Kartik Venkatachalam","Darren Boehning","Ruth Heidelberger"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-12-01T08:00:00Z","date_published":"2018-12-01T08:00:00Z","updated_at":"2026-07-24T05:50:38Z","subjects":["GDAP1","mTORC1 regulation","lysosomal dysfunction","Mucolipidosis Type IV","TRPML1","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/906","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Kartik Venkatachalam","Darren Boehning","Ruth Heidelberger"]},{"key":"dc:creator","label":"Author","values":["Clemons, Kristen","https://orcid.org/0000-0001-9449-896X
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"]},{"key":"dc:title","label":"Title","values":["Involvement of Gdap1 In The Regulation of Mtorc1 Activity In A Drosophila Mliv Model"]}]}],"canonical_facts":{"dc:contributor":["Kartik Venkatachalam","Darren Boehning","Ruth Heidelberger"],"dc:creator":["Clemons, Kristen","https://orcid.org/0000-0001-9449-896X
"],"dc:date.available":["2018-11-30T08:00:00Z"],"dc:description.abstract":["The master regulator of metabolism and growth, mechanistic target of rapamycin complex 1 (mTORC1), is responsible for maintaining metabolic homeostasis by sensing nutrient and energy levels within the cell to promote or inhibit translation and autophagy accordingly. In the childhood neurodevelopmental disorder Mucolipidosis type IV (MLIV), mTORC1 activity is decreased. The underlying mechanism for reduced mTORC1 signaling in MLIV is poorly understood. The gene encoding ganglioside-induced differentiation associated protein 1 (GDAP1) is transcriptionally upregulated in MLIV. This project investigated the involvement of GDAP1 in MLIV disease pathology. Using the UAS/GAL4 system in an established MLIV Drosophila model, we knocked down expression of GDAP1. To determine the effect on mTORC1 activity, we measured phosphorylation levels of the mTORC1 downstream target S6 kinase (S6K) and quantified changes in synaptic growth at the larval neuromuscular junction (NMJ), which is a cell biological readout for mTORC1 activity. We found that knocking down GDAP1 expression can partially suppress the decreased phosphorylated S6K levels and rescue the reduced NMJ synaptic growth that occurs in MLIV Drosophila larvae. These results indicate that GDAP1 plays a role upstream of mTORC1 to affect signaling in MLIV cells. With this knowledge, we draw closer to understanding the dysregulation of mTORC1 signaling that occurs in MLIV patients and gain insight into an incompletely understood mechanism for regulating metabolism.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/906"],"dc:subject":["GDAP1","mTORC1 regulation","lysosomal dysfunction","Mucolipidosis Type IV","TRPML1","Medicine and Health Sciences"],"dc:title":["Involvement of Gdap1 In The Regulation of Mtorc1 Activity In A Drosophila Mliv Model"],"thesis:degree_level":["Thesis (MS)"],"thesis:degree_name":["Masters of Science (MS)"]},"updated_at":"2026-07-24T05:50:38Z"}