{"id":{"repo_id":"dundee","oai_identifier":"oai:discovery.dundee.ac.uk:studenttheses/24313c63-7615-4e76-b92a-07cd2385ac27"},"canonical_url":"https://search.dev.ndltd.org/etd/dundee/oai:discovery.dundee.ac.uk:studenttheses/24313c63-7615-4e76-b92a-07cd2385ac27","repository":{"repo_id":"dundee","name":"University of Dundee","base_url":"https://discovery.dundee.ac.uk/ws/oai"},"display":{"title":"A transthyretin-related gene and a neuroligin-like gene prevent 6-hydroxydopamine-induced dopaminergic neurodegeneration in <i>C. elegans</i>","abstract":"The loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is thought to encompass increased levels of oxidative stress and protein misfolding. We used <i>C. elegans</i> to screen for genes that protect dopaminergic neurons from oxidative stress inflicted by 6-hydroxydopamine (6-OHDA) uptake and isolated the neuroligin-like gene <i>glit-1</i> and the transthyretin-related gene <i>ttr-33</i>. Neuroligins are transmembrane proteins involved in the development and function of synapses. We provide evidence that <i>glit-1</i> and the previously identified tetraspanin <i>tsp-17</i> are associated with the regulation of dopamine turnover, impacting on 6-OHDA uptake into the neurons: <i>glit-1</i> and <i>tsp-17</i> mutant sensitivities to 6-OHDA are not additive and both mutants exhibit signs of increased dopamine signalling. A P<i>glit-1</i>::GFP transcriptional reporter is expressed in the pharynx, intestine and possibly dopaminergic neurons. The second isolated mutant <i>ttr-33</i> in contrast does not display dopamine-related behavioural defects. TTR-33 is likely secreted from the posterior arcade cells in the head and might play a role in cell engulfment, similar to another member of the <i>C. elegans</i> transthyretin-related protein family. <i>C. elegans</i> dopaminergic neurons seem to be phagocytosed after 6-OHDA intoxication as mutations in the engulfment pathway largely suppress neuronal loss. Before being engulfed, dopaminergic neurons likely undergo a necrosis-like cell death − since mutations in apoptosis pathway genes do not prevent, but rather increase neurodegeneration. In addition, the mutated TTR-33 protein might be more prone to aggregation, similar to its human orthologue transthyretin which is associated with amyloid diseases. Indeed, inhibition of the <i>C. elegans</i> unfolded protein response partly alleviates dopaminergic neurodegeneration in the <i>ttr-33</i> mutant. On the organismal level,<i> glit1</i>, <i>tsp-17</i> and <i>ttr-33</i> mutations cause oxidative stress sensitivity but resistance to protein folding stress. In summary, we think that <i>tsp-17</i>, <i>glit-1</i> and <i>ttr-33</i> play a role in the organismal defence against environmental stress.<br/>","abstract_html":"The loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is thought to encompass increased levels of oxidative stress and protein misfolding. We used &lt;i&gt;C. elegans&lt;/i&gt; to screen for genes that protect dopaminergic neurons from oxidative stress inflicted by 6-hydroxydopamine (6-OHDA) uptake and isolated the neuroligin-like gene &lt;i&gt;glit-1&lt;/i&gt; and the transthyretin-related gene &lt;i&gt;ttr-33&lt;/i&gt;. Neuroligins are transmembrane proteins involved in the development and function of synapses. We provide evidence that &lt;i&gt;glit-1&lt;/i&gt; and the previously identified tetraspanin &lt;i&gt;tsp-17&lt;/i&gt; are associated with the regulation of dopamine turnover, impacting on 6-OHDA uptake into the neurons: &lt;i&gt;glit-1&lt;/i&gt; and &lt;i&gt;tsp-17&lt;/i&gt; mutant sensitivities to 6-OHDA are not additive and both mutants exhibit signs of increased dopamine signalling. A P&lt;i&gt;glit-1&lt;/i&gt;::GFP transcriptional reporter is expressed in the pharynx, intestine and possibly dopaminergic neurons. The second isolated mutant &lt;i&gt;ttr-33&lt;/i&gt; in contrast does not display dopamine-related behavioural defects. TTR-33 is likely secreted from the posterior arcade cells in the head and might play a role in cell engulfment, similar to another member of the &lt;i&gt;C. elegans&lt;/i&gt; transthyretin-related protein family. &lt;i&gt;C. elegans&lt;/i&gt; dopaminergic neurons seem to be phagocytosed after 6-OHDA intoxication as mutations in the engulfment pathway largely suppress neuronal loss. Before being engulfed, dopaminergic neurons likely undergo a necrosis-like cell death − since mutations in apoptosis pathway genes do not prevent, but rather increase neurodegeneration. In addition, the mutated TTR-33 protein might be more prone to aggregation, similar to its human orthologue transthyretin which is associated with amyloid diseases. Indeed, inhibition of the &lt;i&gt;C. elegans&lt;/i&gt; unfolded protein response partly alleviates dopaminergic neurodegeneration in the &lt;i&gt;ttr-33&lt;/i&gt; mutant. On the organismal level,&lt;i&gt; glit1&lt;/i&gt;, &lt;i&gt;tsp-17&lt;/i&gt; and &lt;i&gt;ttr-33&lt;/i&gt; mutations cause oxidative stress sensitivity but resistance to protein folding stress. In summary, we think that &lt;i&gt;tsp-17&lt;/i&gt;, &lt;i&gt;glit-1&lt;/i&gt; and &lt;i&gt;ttr-33&lt;/i&gt; play a role in the organismal defence against environmental stress.&lt;br/&gt;","abstract_has_math":false,"creators":["Offenburger, Sarah-Lena"],"institution":"University of Dundee","degree_name":"Doctor of Philosophy","degree_level":"Doctoral Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Gartner, Anton"],"committee_chairs":[],"committee_members":[],"year":2016,"date_issued":"2016","date_published":"2016","updated_at":"2026-07-24T02:08:26Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:discovery.dundee.ac.uk:studenttheses/24313c63-7615-4e76-b92a-07cd2385ac27"],"render_values":[{"text":"oai:discovery.dundee.ac.uk:studenttheses/24313c63-7615-4e76-b92a-07cd2385ac27","href":null,"code":true}]}]},"links":{"outbound_url":"https://discovery.dundee.ac.uk/en/studentTheses/24313c63-7615-4e76-b92a-07cd2385ac27","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Gartner, Anton"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Wellcome Trust","Parkinson’s UK"]},{"key":"dc:creator","label":"Author","values":["Offenburger, Sarah-Lena"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2016"]},{"key":"dc:date.issued","label":"Date","values":["2016"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Gene Regulation and Expression"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Dundee"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://discovery.dundee.ac.uk/en/studentTheses/24313c63-7615-4e76-b92a-07cd2385ac27"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral Thesis"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2018-03-15"]},{"key":"dc:rights.embargoreason","label":"Dc Rights Embargoreason","values":["/dk/atira/pure/core/document/studentthesisembargoreason/commercialexploitation"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:discovery.dundee.ac.uk:studenttheses/24313c63-7615-4e76-b92a-07cd2385ac27","https://discovery.dundee.ac.uk/en/studentTheses/24313c63-7615-4e76-b92a-07cd2385ac27"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://discovery.dundee.ac.uk/files/11472528/Thesis_SarahOffenburger_corrected.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is thought to encompass increased levels of oxidative stress and protein misfolding. We used <i>C. elegans</i> to screen for genes that protect dopaminergic neurons from oxidative stress inflicted by 6-hydroxydopamine (6-OHDA) uptake and isolated the neuroligin-like gene <i>glit-1</i> and the transthyretin-related gene <i>ttr-33</i>. Neuroligins are transmembrane proteins involved in the development and function of synapses. We provide evidence that <i>glit-1</i> and the previously identified tetraspanin <i>tsp-17</i> are associated with the regulation of dopamine turnover, impacting on 6-OHDA uptake into the neurons: <i>glit-1</i> and <i>tsp-17</i> mutant sensitivities to 6-OHDA are not additive and both mutants exhibit signs of increased dopamine signalling. A P<i>glit-1</i>::GFP transcriptional reporter is expressed in the pharynx, intestine and possibly dopaminergic neurons. The second isolated mutant <i>ttr-33</i> in contrast does not display dopamine-related behavioural defects. TTR-33 is likely secreted from the posterior arcade cells in the head and might play a role in cell engulfment, similar to another member of the <i>C. elegans</i> transthyretin-related protein family. <i>C. elegans</i> dopaminergic neurons seem to be phagocytosed after 6-OHDA intoxication as mutations in the engulfment pathway largely suppress neuronal loss. Before being engulfed, dopaminergic neurons likely undergo a necrosis-like cell death − since mutations in apoptosis pathway genes do not prevent, but rather increase neurodegeneration. In addition, the mutated TTR-33 protein might be more prone to aggregation, similar to its human orthologue transthyretin which is associated with amyloid diseases. Indeed, inhibition of the <i>C. elegans</i> unfolded protein response partly alleviates dopaminergic neurodegeneration in the <i>ttr-33</i> mutant. On the organismal level,<i> glit1</i>, <i>tsp-17</i> and <i>ttr-33</i> mutations cause oxidative stress sensitivity but resistance to protein folding stress. In summary, we think that <i>tsp-17</i>, <i>glit-1</i> and <i>ttr-33</i> play a role in the organismal defence against environmental stress.<br/>"]},{"key":"dc:title","label":"Title","values":["A transthyretin-related gene and a neuroligin-like gene prevent 6-hydroxydopamine-induced dopaminergic neurodegeneration in <i>C. elegans</i>"]}]}],"canonical_facts":{"dc:contributor.advisor":["Gartner, Anton"],"dc:contributor.sponsor":["Wellcome Trust","Parkinson’s UK"],"dc:creator":["Offenburger, Sarah-Lena"],"dc:date":["2016"],"dc:date.issued":["2016"],"dc:description.abstract":["The loss of dopaminergic neurons is a hallmark of Parkinson’s disease, the aetiology of which is thought to encompass increased levels of oxidative stress and protein misfolding. We used <i>C. elegans</i> to screen for genes that protect dopaminergic neurons from oxidative stress inflicted by 6-hydroxydopamine (6-OHDA) uptake and isolated the neuroligin-like gene <i>glit-1</i> and the transthyretin-related gene <i>ttr-33</i>. Neuroligins are transmembrane proteins involved in the development and function of synapses. We provide evidence that <i>glit-1</i> and the previously identified tetraspanin <i>tsp-17</i> are associated with the regulation of dopamine turnover, impacting on 6-OHDA uptake into the neurons: <i>glit-1</i> and <i>tsp-17</i> mutant sensitivities to 6-OHDA are not additive and both mutants exhibit signs of increased dopamine signalling. A P<i>glit-1</i>::GFP transcriptional reporter is expressed in the pharynx, intestine and possibly dopaminergic neurons. The second isolated mutant <i>ttr-33</i> in contrast does not display dopamine-related behavioural defects. TTR-33 is likely secreted from the posterior arcade cells in the head and might play a role in cell engulfment, similar to another member of the <i>C. elegans</i> transthyretin-related protein family. <i>C. elegans</i> dopaminergic neurons seem to be phagocytosed after 6-OHDA intoxication as mutations in the engulfment pathway largely suppress neuronal loss. Before being engulfed, dopaminergic neurons likely undergo a necrosis-like cell death − since mutations in apoptosis pathway genes do not prevent, but rather increase neurodegeneration. In addition, the mutated TTR-33 protein might be more prone to aggregation, similar to its human orthologue transthyretin which is associated with amyloid diseases. Indeed, inhibition of the <i>C. elegans</i> unfolded protein response partly alleviates dopaminergic neurodegeneration in the <i>ttr-33</i> mutant. On the organismal level,<i> glit1</i>, <i>tsp-17</i> and <i>ttr-33</i> mutations cause oxidative stress sensitivity but resistance to protein folding stress. In summary, we think that <i>tsp-17</i>, <i>glit-1</i> and <i>ttr-33</i> play a role in the organismal defence against environmental stress.<br/>"],"dc:identifier":["oai:discovery.dundee.ac.uk:studenttheses/24313c63-7615-4e76-b92a-07cd2385ac27","https://discovery.dundee.ac.uk/en/studentTheses/24313c63-7615-4e76-b92a-07cd2385ac27"],"dc:identifier.uri":["https://discovery.dundee.ac.uk/files/11472528/Thesis_SarahOffenburger_corrected.pdf"],"dc:language":["eng"],"dc:publisher.department":["Gene Regulation and Expression"],"dc:publisher.institution":["University of Dundee"],"dc:relation.isreferencedby":["https://discovery.dundee.ac.uk/en/studentTheses/24313c63-7615-4e76-b92a-07cd2385ac27"],"dc:rights.embargodate":["2018-03-15"],"dc:rights.embargoreason":["/dk/atira/pure/core/document/studentthesisembargoreason/commercialexploitation"],"dc:title":["A transthyretin-related gene and a neuroligin-like gene prevent 6-hydroxydopamine-induced dopaminergic neurodegeneration in <i>C. elegans</i>"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral Thesis"],"dc:type.qualificationname":["Doctor of Philosophy"]},"updated_at":"2026-07-24T02:08:26Z"}