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O efeito do THC na agregação da alfa-sinucleína e o seu uso como substância medicamentosa no tratamento da Doença de Parkinson
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A Doença de Parkinson (DP) é uma patologia neurodegenerativa progressiva marcada pela degeneração dos neurónios dopaminérgicos da substantia nigra pars compacta e pela acumulação de agregados de alfa-sinucleína (αSyn). Embora os tratamentos atuais controlem os sintomas motores, não impedem a progressão da doença, tornando necessária a investigação de novas abordagens terapêuticas.
O Δ9-tetrahidrocanabinol (Δ9THC) tem demonstrado propriedades neuroprotetoras, incluindo efeitos antioxidantes, anti-inflamatórios e moduladores da autofagia. No entanto, permanece pouco estudado o seu impacto direto (ou o dos seus metabolitos, como o Δ9THCA) na estrutura de proteínas envolvidas na patogénese da DP, como a αSyn.
Neste estudo, foi produzida αSyn humana recombinante e purificado Δ9THCA por HPLC, avaliando-se por dicroísmo circular (CD) o efeito deste composto na estrutura secundária da proteína. Como a produção de aSyn é um processo moroso, começámos por testar a hipótese do Δ9THCA interaccionar com uma proteína adquirida comercialmente, a BSA.
Os resultados mostraram que o Δ9THCA estabiliza a BSA e aumenta o seu conteúdo em hélice-α. No caso da αSyn, verificou-se uma redução consistente da fração desordenada (de ~0,43 para ~0,31), indicando uma modulação conformacional discreta, mas mensurável, mantida durante pelo menos 24 horas. Apesar de não induzir a formação de estruturas rigidamente definidas, o Δ9THCA parece alterar a flexibilidade conformacional da αSyn, podendo alterar a sua tendência para agregação.
Este trabalho sugere que o Δ9THCA pode interferir com o estado estrutural da αSyn, justificando investigações adicionais sobre o seu impacto na agregação proteica e em modelos celulares. Os resultados contribuem também para o debate científico e legal sobre o potencial terapêutico dos canabinoides na DP, cuja aplicação clínica futura requer validação adicional in vitro, in vivo e em contexto clínico.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of alpha-synuclein (αSyn) aggregates. Although current therapies alleviate motor symptoms, they do not halt disease progression, highlighting the need for new therapeutic strategies. Δ9-tetrahydrocannabinol (Δ9THC) exhibits documented neuroprotective properties, including antioxidant, anti-inflammatory and autophagy-modulating effects. However, the direct impact of this cannabinoid or its metabolites, such as Δ9THCA, on proteins implicated in PD pathology, such as αSyn, remains poorly explored. In this study, recombinant human αSyn was produced and purified, and Δ9THCA was purified by HPLC. Circular dichroism (CD) spectroscopy was used to evaluate the effect of Δ9THCA on the secondary structure of αSyn. Since the production of αSyn is a time-consuming process, we started by testing the hypothesis that Δ9THC interacts with a commercial acquired protein, BSA. Results showed that Δ9THCA stabilizes BSA and increases its α-helical content. In the case of αSyn, a consistent reduction of the disordered fraction was observed (from ~0.43 to ~0.31), indicating a subtle but measurable conformational modulation that persisted for at least 24 hours. Although no highly ordered structures were induced, Δ9THCA appeared to alter the conformational flexibility of αSyn, potentially affecting its aggregation dynamics. These findings suggest that Δ9THCA may influence the structural state of αSyn, supporting further investigation into its effects on protein aggregation and in cellular models. This study also contributes to the scientific and legal discussion surrounding the therapeutic potential of cannabinoids in PD, whose clinical application requires additional in vitro, in vivo, and clinical evidence.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of alpha-synuclein (αSyn) aggregates. Although current therapies alleviate motor symptoms, they do not halt disease progression, highlighting the need for new therapeutic strategies. Δ9-tetrahydrocannabinol (Δ9THC) exhibits documented neuroprotective properties, including antioxidant, anti-inflammatory and autophagy-modulating effects. However, the direct impact of this cannabinoid or its metabolites, such as Δ9THCA, on proteins implicated in PD pathology, such as αSyn, remains poorly explored. In this study, recombinant human αSyn was produced and purified, and Δ9THCA was purified by HPLC. Circular dichroism (CD) spectroscopy was used to evaluate the effect of Δ9THCA on the secondary structure of αSyn. Since the production of αSyn is a time-consuming process, we started by testing the hypothesis that Δ9THC interacts with a commercial acquired protein, BSA. Results showed that Δ9THCA stabilizes BSA and increases its α-helical content. In the case of αSyn, a consistent reduction of the disordered fraction was observed (from ~0.43 to ~0.31), indicating a subtle but measurable conformational modulation that persisted for at least 24 hours. Although no highly ordered structures were induced, Δ9THCA appeared to alter the conformational flexibility of αSyn, potentially affecting its aggregation dynamics. These findings suggest that Δ9THCA may influence the structural state of αSyn, supporting further investigation into its effects on protein aggregation and in cellular models. This study also contributes to the scientific and legal discussion surrounding the therapeutic potential of cannabinoids in PD, whose clinical application requires additional in vitro, in vivo, and clinical evidence.
Descrição
Dissertação para obtenção do grau de Mestre no Instituto Universitário Egas Moniz
Palavras-chave
Alfa-sinucleína THC Doença de Parkinson Legislação