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      • Graduate Program in Materials Science and Nanotechnology - Master's degree
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      • University Library
      • Bilkent Theses
      • Theses - Graduate Program in Materials Science and Nanotechnology
      • Graduate Program in Materials Science and Nanotechnology - Master's degree
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      Peptide based ligand discovery to prevent protein aggregation in neurodegenerative disease conditions

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      Embargo Lift Date: 2020-03-13
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      Author(s)
      Beğli, Özge
      Advisor
      Şeker, Urartu Özgür Şafak
      Date
      2019-09
      Publisher
      Bilkent University
      Language
      English
      Type
      Thesis
      Item Usage Stats
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      Abstract
      Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are cognitively and physically debilitating and progressive diseases due to the gradual and irreversible loss of discrete neuronal populations in the brain. In addition to millions of people worldwide suffering from them, the prevalence of the neurodegenerative diseases dramatically increases with the increasing lifespan of the population. Most of the current therapeutic strategies either target toxic aggregates in neurons or support the healthy cells in diseased region. However, these interventions provide only symptomatic relief and deceleration of disease progression. Besides, aggregation involves a locking phase in which irreversible transition of soluble monomeric and oligomeric molecules into insoluble fibrous structures occurs. During aggregation, fragmentation of mature fibrils leads to the formation of new oligomeric structures possessing seeding activity. The seeds behaving as a nucleation unit trigger other structures to join the accumulated proteins. Synthetic biology is an emerging field that suggests therapeutic solutions for several diseases. Development of synthetic proteins such as artificial transcription factors and improved antibodies, artificial cell transplants with controlled secretion, designed inhibitory RNA molecules and antisense oligonucleotides, gene circuits and logic gates, synthetic viruses as an advanced delivery system and genome editing technologies using programmable nucleases are revolutionary approaches for the diagnosis and treatment of diseases. With the utilization of a variety of advanced tools, synthetic biology is extremely promising to treat neurodegenerative disorders too. In this study, biotechnological approaches and tools such as gene cloning, yeast surface display and phage display library have been used to target neurodegenerative proteins before aggregation takes place. Neurodegenerative proteins were cloned into a plasmid DNA within bacteria and displayed on the surface of Saccharomyces cerevisiae cells. A phage display library has been screened against those neurodegenerative proteins and binding peptides of these proteins have been selected following recursive rounds of binding and washing steps. Peptides that bind to neurodegenerative proteins with high affinity possess the potential to block them and prevent the initiation of aggregation. Beside to the promising results of neuroprotective and neurorestorative interventions, this strategy can provide prevention of aggregation which is the underlying cause of neurodegeneration.
      Keywords
      Neurodegenerative diseases
      Synthetic biology
      Amyloid
      Yeast surface display
      Phage library display
      Protein-ligand interactions
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      http://hdl.handle.net/11693/52447
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