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- The cholesterol 24-hydroxylase activates autophagy and decreases mutant huntingtin build-up in a neuroblastoma culture model of Huntington’s diseasePublication . Nóbrega, Clévio; Conceição, André; Costa, Rafael G; Koppenol, Rebekah; Sequeira, Raquel L.; Nunes, Ricardo; Carmo-Silva, Sara; Marcelo, Adriana; Matos, Carlos A; Betuing, Sandrine; Caboche, Jocelyne; Cartier, Nathalie; Alves, SandroObjective Compromised brain cholesterol turnover and altered regulation of brain cholesterol metabolism have been allied with some neurodegenerative diseases, including Huntington’s disease (HD). Following our previous studies in HD, in this study we aim to investigate in vitro in a neuroblastoma cellular model of HD, the effect of CYP46A1 overexpression, an essential enzyme in cholesterol metabolism, on huntingtin aggregation and levels. Results We found that CYP46A1 reduces the quantity and size of mutant huntingtin aggregates in cells, as well as the levels of mutant huntingtin protein. Additionally, our results suggest that the observed beneficial effects of CYP46A1 in HD cells are linked to the activation of autophagy. Taken together, our results further demonstrate that CYP46A1 is a pertinent target to counteract HD progression.
- On the role of RNA binding proteins in polyglutamine diseases: from pathogenesis to therapeuticsPublication . Conceição, André; Koppenol, Rebekah; Nóbrega, ClévioPolyglutamine (polyQ) diseases are a group of different neurodegenerative disorders characterized by an abnormal expansion of the trinucleotide cytosine-adenine-guanine (CAG) within coding regions of each disease-associated gene. The abnormal expansion translates into a protein bearing an abnormally long tract of glutamines. The expanded proteins are prone to aggregate, promote aberrant interaction with other proteins and mRNAs and contribute to cellular pathway disruption (Matos et al., 2019). To date, nine different polyQ diseases are described, including among others, Huntington’s disease, and six different spinocerebellar ataxias (SCA). Patients affected by polyQ diseases, suffer a myriad of motor symptoms that include ataxia, dysphagia, tremors, dysarthria, and even dementia. Unfortunately, there is no cure nor treatment able to delay the disease and patients rely only on symptomatic and supportive treatments culminating in premature death (Takahashi et al., 2010).