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Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach
Thesis (PhD)--Stellenbosch University, 2025.
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| Format: | Thesis |
| Language: | English |
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Stellenbosch : Stellenbosch University
2025
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| _version_ | 1867614118653984768 |
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| access_status_str | Open Access |
| author | Coetzee, Johanna Adriana |
| author2 | Smith, Carine |
| author_browse | Coetzee, Johanna Adriana Smith, Carine |
| author_facet | Smith, Carine Coetzee, Johanna Adriana |
| author_sort | Coetzee, Johanna Adriana |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (PhD)--Stellenbosch University, 2025. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/134575 |
| institution | Stellenbosch University (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:46:57.306Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/134575 Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach Coetzee, Johanna Adriana Smith, Carine Pretorius, Lesha Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine. Division of Clinical Pharmacology. Autism spectrum disorder Mitochondrial pathology Chronic diseases Neuropharmacology Thesis (PhD)--Stellenbosch University, 2025. Coetzee, J. A. 2025. Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach. Unpublished doctoral dissertation. Stellenbosch: Stellenbosch University [online]. Available: https://scholar.sun.ac.za/items/eeca5fd3-19ee-4a5f-8d73-e25aad201b39 ENGLISH ABSTRACT: Autism spectrum disorders (ASD) - the increasingly prevalent, highly heritable group of neurodevelopmental disorders - are primarily defined by their core behavioural characteristics. In addition, a high prevalence of comorbid conditions — particularly anxiety and gastrointestinal (GI) dysfunction — significantly contributes to disease burden. Mitochondrial dysfunction has emerged as a central pathophysiological mechanism, implicated in both neuronal network disruptions and comorbidities associated with ASD. Despite this, no approved pharmacological treatment targets the full spectrum of ASD-related symptoms. Given the absence of ASD-specific treatments and the limited efficacy of current pharmacological interventions in addressing the full spectrum of symptoms, this thesis aimed to use a larval zebrafish model of ASD to further elucidate mitochondrial dysfunction and to evaluate the therapeutic potential of drug candidates and its capability of modulating mitochondrial function, as well as behavioural and gut health outcome. Firstly, a valproic acid (VPA)-induced larval zebrafish model of ASD was optimized and characterized to confirm the presence of clinically relevant phenotypes centrally (craniofacial abnormalities, altered NLGN3 expression, anxiety-like behaviour) and peripherally (gastrointestinal dysregulation). Secondly, a multimodal imaging approach was employed to investigate mitochondrial dysfunction in more detail – this entailed the combination of complementary microscopy techniques to span the resolution spectrum from whole-body expression to subcellular mitochondrial morphology. This was supplemented with respirometry and redox profiling to functionally assess mitochondrial respiration and oxidative status. Finally, drug screening was performed using both a pharmaceutical (VPA) and biological compounds (polyamines), with the aim of identifying candidates capable of mitigating ASD- associated behavioural and physiological impairments through modulation of mitochondrial function. Data generated confirmed that the VPA-induced zebrafish larval model successfully recapitulated key features of ASD, including both core markers (e.g. dysregulated NLGN3 expression, craniofacial abnormalities) and clinically relevant comorbidities (e.g. anxiety like behaviour and dysregulation at the level of the gastrointestinal tract). High-resolution imaging revealed notable changes in mitochondrial distribution, organisation and morphology, particularly in the gut. The parallel assessment of central and peripheral compartments to include the gut, is novel, and demonstrated increased lysosomal activity in this compartment, which may be linked to ASD- associated mitochondrial dysregulation. This data contributes to our understanding of mitochondrial dysfunction in ASD and warrant further studies to identify therapeutic targets in this context. In terms of therapeutics development, it was demonstrated that agmatine (AGM) effectively ameliorated anxiety-like behaviours and restored gastrointestinal lysosomal activity, while modulating all mitochondrial parameters across compartments. In conclusion, this dissertation contributes significantly to our understanding of the complex nature of mitochondrial dysfunction in ASD, with novel contribution to the gut context. In addition, the value of zebrafish larvae as a research tool to accurately recapitulates both core and comorbid ASD phenotypes is highlighted. From a therapeutic standpoint, AGM shows promise as a dual-target therapeutic—acting on both central behaviours and peripheral physiology by modulating mitochondrial function. AFRIKAANSE OPSOMMING: Geen opsomming beskikbaar. Doctoral 2025-12-15T06:53:31Z 2025-12-15T06:53:31Z 2025-12 Thesis https://scholar.sun.ac.za/handle/10019.1/134575 en Stellenbosch University 144 pages : illustrations application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | Autism spectrum disorder Mitochondrial pathology Chronic diseases Neuropharmacology Coetzee, Johanna Adriana Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach |
| title | Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach |
| title_full | Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach |
| title_fullStr | Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach |
| title_full_unstemmed | Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach |
| title_short | Modelling non-communicable diseases in autism spectrum disorder: a pharmacological approach |
| title_sort | modelling non communicable diseases in autism spectrum disorder a pharmacological approach |
| topic | Autism spectrum disorder Mitochondrial pathology Chronic diseases Neuropharmacology |
| url | https://scholar.sun.ac.za/handle/10019.1/134575 |
| work_keys_str_mv | AT coetzeejohannaadriana modellingnoncommunicablediseasesinautismspectrumdisorderapharmacologicalapproach |