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The effects of radiation on amyloids and cells experimentally and modeled using the TOPAS framework
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Resumo(s)
Neurodegenerative disorders are characterised by the presence of protein aggregates called amyloids that
are related to neuroinflammation and oxidative stress. We hypothesised radiation as a possible treatment for neurodegeneration, destroying the amyloid structures either by breaking the chemical bonds
or inducing cellular mechanisms of degradation. Both experimental work and Monte Carlo simulations
were conducted. HeLa human cervical cancer and two stains of rat glioblastoma C6 cells were irradiated
with 60Co sources (1-10 Gy). The dosimetry of the irradiator was studied with Monte Carlo simulations. Oxidative stress was assessed with the DCFHDA assay and shown to persist until 120 minutes
after irradiation, probably due to mitochondrial damage. Moreover, C6 cells were significantly more
sensitive to ionising radiation than HeLa cells. We also evaluated the effect of radiation on amyloids
formed by huntingtin, a protein causing Huntington’s disease, when it was transiently transfected into
HeLa cells. Huntingtin expression levels were significantly lower 24 hours after receiving 5 and 10 Gy.
In another model of neurodegenerative disorders, this time caused by aggregation of endogenous intermediate filaments, radiation decreased the expression levels of the intermediate filament nestin. To study
the effect of protons on amyloids, we simulated amyloid damage using the TOPAS MC toolkit. Lower
proton energies induced more bond breaks, with electrons being the main contributors, especially for
higher doses. Hydrogen bonds were the target of 5-15 % of all breaks. Our results also indicated that
reactive oxygen species induced by water radiolysis are significant to amyloid structural modifications.
We also concluded that irradiating cell cultures with an 8 MeV proton beam would give high variability
results due to the heterogeneity of dose distribution. Our research could shed some light on mechanisms
underlying the positive results of radiation on amyloidosis and lay the groundwork for radiotherapy for
neurodegenerative disorders.
Descrição
Tese de mestrado, Engenharia Biomédica e Biofísica, 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Doenças neurodegenerativas amiloidose radiação ionizante simulações Monte Carlo terapia de protões Teses de mestrado - 2023