Thesis
Upregulation of beclin1-mediated autophagy via antisense oligonucleotides to promote clearance of TDP-43 aggregates in amyotrophic lateral sclerosis cell models
Honours, Murdoch University
2023
Abstract
Amyotrophic lateral sclerosis is a debilitating and ultimately fatal neurodegenerative disease that is characterised by the loss of motor neurons, leading to eventual paralysis. In Australia, Riluzole is currently the only medication approved to treat amyotrophic lateral sclerosis, however it prolongs survival by just a few months and there is no curative treatment available. Accumulation of unwanted proteins (proteinopathy) is one of the main pathways of pathogenesis in most neurodegenerative disease, with TDP-43 aggregates being present in ~97% of amyotrophic lateral sclerosis cases; clearance of these aggregates through upregulation of autophagy has been proposed as a treatment. This study aimed to assess the efficacy of a novel drug candidate for ALS to clear TDP-43 aggregates via the autophagy pathway in an ALS HEK293 cell model. Our drug candidate is an antisense oligonucleotide synthesised as a phosphorodiamidate morpholino oligomer that activates the autophagy pathway via regulation of Beclin-1 (BECN1) RNA transcripts. Our findings indicate that our drug candidate excludes the targeted exons as expected and thereby increases the level of active BECN1 and activates autophagy, leading to TDP-43 clearance. The data presented in this manuscript is preliminary and thus further biological replicates are required to validate the results presented.
Details
- Title
- Upregulation of beclin1-mediated autophagy via antisense oligonucleotides to promote clearance of TDP-43 aggregates in amyotrophic lateral sclerosis cell models
- Authors/Creators
- Sydney J Roldan
- Contributors
- Sarah Lyn Rea (Supervisor) - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsIanthe Pitout (Supervisor) - Murdoch University, Centre for Molecular Medicine and Innovative Therapeutics
- Awarding Institution
- Murdoch University; Honours
- Identifiers
- 991005662068507891
- Murdoch Affiliation
- School of Medical, Molecular and Forensic Sciences
- Resource Type
- Thesis
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