Stress granules in Polyglutamine diseases: new targets for therapeutic intervention

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Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy

Publication . Marcelo, Adriana; Afonso, Inês T.; Afonso-Reis, Ricardo; Brito, David V. C.; Costa, Rafael G.; Rosa, Ana; Alves-Cruzeiro, João; Ferreira, Benedita; Henriques, Carina; Nobre, Rui J.; Matos, Carlos A; de Almeida, Luís Pereira; Nóbrega, Clévio

Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several europathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients’ striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.

2021-11Journal article

Open access

Stress granules in Polyglutamine diseases: new targets for therapeutic intervention?

Publication . Marcelo, Adriana Isabel do Vale; Nóbrega, Clévio; Almeida, Luís Pereira de

Polyglutamine (PolyQ) diseases are a group of hereditary and incurable neurodegenerative pathologies, caused by abnormal expansion of CAG trinucleotide repeats in the disease-causing genes. In these disorders, the formation of toxic aggregated species from the expanded protein leads to dysfunction of several biological systems, ultimately resulting in neuronal degeneration and death widespread across different brain regions. Dysfunction of cellular pathways also correlates with stress responses, such as the formation of stress granules (SGs). Recently, multiple evidence suggested that SGs and its components play a role in the pathogenesis of PolyQ diseases. Therefore, the general goal of this project was to clarify the SGs role in the context of PolyQ diseases pathogenesis, trying to identify new pathways and targets for a therapeutic intervention, using spinocerebellar ataxia type 3 (SCA3) and type 2 (SCA2) as PolyQ disease models. We found that several SGs components have their gene expression levels altered in these two diseases, including regulated heat stable protein 1 (CARHSP1) and Pumilio homolog 1 (PUM1), which have their levels upregulated in SCA3 and SCA2 diseases. We found that the downregulation of CARHSP1 resulted in reduced mutant protein aggregation in SCA3 cellular and mouse models, as well as amelioration of motor and neuropathological abnormalities. On the other hand, knockdown of PUM1 levels led to increased aggregation of polyQ-expanded protein, as well as worsening of motor deficits in mouse models of SCA3 disease. We further assessed the downregulation of CARHP1 in a novel striatal lentiviral mouse of SCA2, although no alterations in neuropathological features were observed. Overall, our study contributes to the putative involvement of SGs in PolyQ disease and showed that the modulation of CARHSP1 SGs component could be potential therapeutic approach for SCA3 disease. Future studies are needed to fully understand SGs and its components importance in the context of PolyQ and other neurodegenerative diseases.

2022-01-26Doctoral thesis

Open access

MSGP: the first database of the protein components of the mammalian stress granules

Publication . Nunes, Catarina; Mestre, Isa; Marcelo, Adriana; Koppenol, Rebekah; Matos, Carlos A.; Nóbrega, Clévio

In response to different stress stimuli, cells transiently form stress granules (SGs) in order to protect themselves and re-establish homeostasis. Besides these important cellular functions, SGs are now being implicated in different human diseases, such as neurodegenerative disorders and cancer. SGs are ribonucleoprotein granules, constituted by a variety of different types of proteins, RNAs, factors involved in translation and signaling molecules, being capable of regulating mRNA translation to facilitate stress response. However, until now a complete list of the SG components has not been available. Therefore, we aimer at identifying and linting in an open access database all the proteins described so far as components of SGs. The identification was made through an exhaustive search of studies listed in PubMed and double checked. Moreover, for each identified protein several details were also gathered from public databases, such as the molecular function, the cell types in which they were detected, the type of stress stimuli used to induce SG formation and the reference of the study describing the recruitment of the component to SGs. Expression levels in the context of different neurodegenerative diseases were also obtained and are also described in the database. The Mammalian Stress Granules Proteome is available at https://msgp.pt/, being a new and unique open access online database, the first to list all the protein components of the SGs identified so far. The database constitutes an important and valuable tool for researchers in this research area of growing interest.

2019Journal article

Open access