{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/341644"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/341644","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Understanding the molecular bases of neurodegeneration: From the structural characterisation of the aggregates to the establishment of an iPSC-derived neuronal model","abstract":"Neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are associated with the process of protein misfolding and aggregation. The molecular mechanisms by which this process causes the progressive loss of neurons characteristic of these conditions, however, are still largely unknown. To address this problem, biophysical studies can play a major role. By adopting this approach, we study the soluble oligomeric species formed during the aggregation process of the amyloid beta (Aβ) peptide, which are thought to play a critical role in the pathogenesis of AD, and to be a main source of cellular dysfunction. In the first part of the thesis, we characterize the physio-chemical properties and the biological activity of oligomeric populations resulting from the aggregation of a set of four Aβ40 variants, each carrying a familial mutation with the aim to study their structures. We then employ neuroblastoma cell lines to explore the relationship between the cellular toxicity and the structural and physio-chemical properties of these oligomeric species. Alongside this, the development of accurate disease models is necessary for the elucidation of the biological mechanisms central to the pathology, and for the discovery of effective therapies targeting such mechanisms. Therefore, in the second part of this thesis, we establish and characterise three pluripotent stem cell (iPSCs) clones containing the familiar PD mutation A53T in α-synuclein. We then proceed to differentiate these lines into dopaminergic neurons (DaNs) before characterising them to show that they are a suitable model to study PD. Having established these disease models, we explore the effects of various external stressors on the aggregation of α-synuclein in the DaNs. Taken together, the results that we report in this work contribute to linking the molecular process of protein aggregation to its consequences at the cellular level.","abstract_html":"Neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are associated with the process of protein misfolding and aggregation. The molecular mechanisms by which this process causes the progressive loss of neurons characteristic of these conditions, however, are still largely unknown. To address this problem, biophysical studies can play a major role. By adopting this approach, we study the soluble oligomeric species formed during the aggregation process of the amyloid beta (Aβ) peptide, which are thought to play a critical role in the pathogenesis of AD, and to be a main source of cellular dysfunction. In the first part of the thesis, we characterize the physio-chemical properties and the biological activity of oligomeric populations resulting from the aggregation of a set of four Aβ40 variants, each carrying a familial mutation with the aim to study their structures. We then employ neuroblastoma cell lines to explore the relationship between the cellular toxicity and the structural and physio-chemical properties of these oligomeric species. Alongside this, the development of accurate disease models is necessary for the elucidation of the biological mechanisms central to the pathology, and for the discovery of effective therapies targeting such mechanisms. Therefore, in the second part of this thesis, we establish and characterise three pluripotent stem cell (iPSCs) clones containing the familiar PD mutation A53T in α-synuclein. We then proceed to differentiate these lines into dopaminergic neurons (DaNs) before characterising them to show that they are a suitable model to study PD. Having established these disease models, we explore the effects of various external stressors on the aggregation of α-synuclein in the DaNs. Taken together, the results that we report in this work contribute to linking the molecular process of protein aggregation to its consequences at the cellular level.","abstract_has_math":false,"creators":["Pisani, Katarina"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Vendruscolo, Michele"],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-09-30","date_published":"2021-09-30","updated_at":"2026-07-22T22:24:24Z","subjects":["amyloid aggregation","iPSC-derived neuronal model","neurodegeneration"],"languages":["eng"],"rights":[],"rights_urls":["https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.89070","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Vendruscolo, Michele"]},{"key":"dc:creator","label":"Author","values":["Pisani, Katarina"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2021-09-30"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/341644"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["amyloid aggregation","iPSC-derived neuronal model","neurodegeneration"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.89070"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/5052c35f-95c3-4d65-9a31-9cdd6588b60a/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are associated with the process of protein misfolding and aggregation. The molecular mechanisms by which this process causes the progressive loss of neurons characteristic of these conditions, however, are still largely unknown. To address this problem, biophysical studies can play a major role. By adopting this approach, we study the soluble oligomeric species formed during the aggregation process of the amyloid beta (Aβ) peptide, which are thought to play a critical role in the pathogenesis of AD, and to be a main source of cellular dysfunction. In the first part of the thesis, we characterize the physio-chemical properties and the biological activity of oligomeric populations resulting from the aggregation of a set of four Aβ40 variants, each carrying a familial mutation with the aim to study their structures. We then employ neuroblastoma cell lines to explore the relationship between the cellular toxicity and the structural and physio-chemical properties of these oligomeric species. Alongside this, the development of accurate disease models is necessary for the elucidation of the biological mechanisms central to the pathology, and for the discovery of effective therapies targeting such mechanisms. Therefore, in the second part of this thesis, we establish and characterise three pluripotent stem cell (iPSCs) clones containing the familiar PD mutation A53T in α-synuclein. We then proceed to differentiate these lines into dopaminergic neurons (DaNs) before characterising them to show that they are a suitable model to study PD. Having established these disease models, we explore the effects of various external stressors on the aggregation of α-synuclein in the DaNs. Taken together, the results that we report in this work contribute to linking the molecular process of protein aggregation to its consequences at the cellular level."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["67a34195c93e57700681c80307426740"]},{"key":"dc:title","label":"Title","values":["Understanding the molecular bases of neurodegeneration: From the structural characterisation of the aggregates to the establishment of an iPSC-derived neuronal model"]}]}],"canonical_facts":{"dc:contributor.advisor":["Vendruscolo, Michele"],"dc:creator":["Pisani, Katarina"],"dc:date.issued":["2021-09-30"],"dc:description.abstract":["Neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), are associated with the process of protein misfolding and aggregation. The molecular mechanisms by which this process causes the progressive loss of neurons characteristic of these conditions, however, are still largely unknown. To address this problem, biophysical studies can play a major role. By adopting this approach, we study the soluble oligomeric species formed during the aggregation process of the amyloid beta (Aβ) peptide, which are thought to play a critical role in the pathogenesis of AD, and to be a main source of cellular dysfunction. In the first part of the thesis, we characterize the physio-chemical properties and the biological activity of oligomeric populations resulting from the aggregation of a set of four Aβ40 variants, each carrying a familial mutation with the aim to study their structures. We then employ neuroblastoma cell lines to explore the relationship between the cellular toxicity and the structural and physio-chemical properties of these oligomeric species. Alongside this, the development of accurate disease models is necessary for the elucidation of the biological mechanisms central to the pathology, and for the discovery of effective therapies targeting such mechanisms. Therefore, in the second part of this thesis, we establish and characterise three pluripotent stem cell (iPSCs) clones containing the familiar PD mutation A53T in α-synuclein. We then proceed to differentiate these lines into dopaminergic neurons (DaNs) before characterising them to show that they are a suitable model to study PD. Having established these disease models, we explore the effects of various external stressors on the aggregation of α-synuclein in the DaNs. Taken together, the results that we report in this work contribute to linking the molecular process of protein aggregation to its consequences at the cellular level."],"dc:format.checksum.md5":["67a34195c93e57700681c80307426740"],"dc:identifier.doi":["10.17863/CAM.89070"],"dc:identifier.uri":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/5052c35f-95c3-4d65-9a31-9cdd6588b60a/download"],"dc:language":["eng"],"dc:publisher.institution":["University of Cambridge"],"dc:relation.isreferencedby.uri":["https://www.repository.cam.ac.uk/handle/1810/341644"],"dc:rights":["https://www.rioxx.net/licenses/all-rights-reserved/"],"dc:subject":["amyloid aggregation","iPSC-derived neuronal model","neurodegeneration"],"dc:title":["Understanding the molecular bases of neurodegeneration: From the structural characterisation of the aggregates to the establishment of an iPSC-derived neuronal model"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-22T22:24:24Z"}