Cholesterol in excess in the brain has an impact in neurodegenerative diseases
A study coordinated by researchers at the Center for Neuroscience and Cell Biology of the University of Coimbra (CNC-UC) has demonstrated in which the cleaning of excessive cholesterol in our brain have an impact in the therapy of spinocerebellar ataxias, such as in Machado-Joseph’s Disease.

Cholesterol

In the study, published in the highly conceited Acta Neuropathologica, the research team evaluated the role of the CYP46A1 (a protein responsible for transforming excessive cholesterol in a process known as hydroxylation) in the type 3 spinocerebellar ataxia, known as Machado Joseph’s Disease (MJD), which is caused by the accumulation of mutated ataxin-3. When the function of CYP46A1 is found diminished, it leads to the excessive of cholesterol  accumulation (a determining molecule in the transmission of information between neurons), a situation associated with the onset of neurodegenerative diseases. Therefore, the study aimed to evaluate if the excessive accumulation of cholesterol in the brain could be related to the accumulation of mutated ataxin-3.

“There were evidences that the reduction of CYP46A1 was associated with other neurodegenerative diseases, such as Alzheimer and Huntington, and were characterized by the accumulation of mutated proteins. With this study, we wanted to check whether the same would be observed in spinocerebellar ataxias, especially in MJD”, explains one the coordinators of the study, Luís Pereira de Almeida, researcher at CNC and Professor at the Faculty of Pharmacy of the University of Coimbra. “As we observed that this protein was diminished in the brains of patients and animal models for the disease, we wanted to assess if, by re-adding we could “clean” the cholesterol in excess, as well as the mutated ataxin-3, and the associated neurodegeneration”, adds the researcher who led the project, in collaboration with Nathalie Cartier (from Institut National de la Santé et al Recherche Médicale, France) and Sandro Alves (Institut du Cerveau et de la Moelle Epinière, also from France).

In this study, researchers observed that, by removing CYP46A1 in healthy animals, a neurodegeneration similar to MJD was observed. When the re-added the protein, there was an improvement associated with neuronal function, and animal motor capacity, associated with a reduction in ataxin-3 toxic aggregates. “We were able to alleviate the symptoms of the disease in 2 different animal models”, refers the researcher. “We observed an activating role of CYP46A1 in autophagy (our cells’ recycling process), whose activation we had previously shown to be extremely important in the clean-up of mutated ataxin-3 agglomerates”.

The next step of the research team will try to understand better how does the cholesterol cleaning and autophagy are connected with the accumulation of mutated ataxin-3. By understanding these processes, there may be a big clinical impact in neurodegenerative diseases: “We might have a therapeutic strategy that may be more general, which may not be able to heal, but at least promote some sort of relief in these diseases, using simpler and cheaper methods”, concludes Luís de Almeida.


The study “Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia” is available in https://doi.org/10.1007/s00401-019-02019-7, and has Liliana Mendonça (CNC researcher) and Clévio Nóbrega (CNC collaborator and coordinator at the Center for Biomedical Research (CBMR) at the University of Algarve) has co-principal authors. Other researchers at CNC which also participated were Sandra Tomé and Carlos Matos, and the team also comprised of researchers from CBMR, Universidade do Algarve, and from French and Dutch research centers.

The study was financed by the European Comission (JPND co-fund program), by the European Fund for Regional Development (FEDER), COMPETE 2020, Foundation for Science and Technology (FCT), NeuroATRIS, Richard Chin and Lily Lock Research Fund for the Machado-Joseph’s Disease, National Ataxia Foundation, and by the French Medical Research Foundation.


Credits: João Cardoso, Luís de Almeida, Rui Simões

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Financiado por Fundos FEDER através do Programa Operacional Factores de Competitividade – COMPETE 2020 e por Fundos Nacionais através da FCT – Fundação para a Ciência e a Tecnologia no âmbito do projecto Estratégico com referência atribuida pelo COMPETE: POCI-01-0145-FEDER-007440

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