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- From the disruption of RNA metabolism to the targeting of RNA‐binding proteins: the case of polyglutamine spinocerebellar ataxiasPublication . Gomes, Tiago; Nóbrega, ClévioPolyglutamine spinocerebellar ataxias (PolyQ SCAs) represent a group of monogenetic diseases in which the expanded polyglutamine repeats give rise to a mutated protein. The abnormally expanded polyglutamine protein produces aggregates and toxic species, causing neuronal dysfunction and neuronal death. The main symptoms of these disorders include progressive ataxia, motor dysfunction, oculomotor impairment, and swallowing problems. Nowadays, the current treatments are restricted to symptomatic alleviation, and no existing therapeutic strategies can reduce or stop the disease progression. Even though the origin of these disorders has been associated with polyglutamine-induced toxicity, RNA toxicity has recently gained relevance in polyQ SCAs molecular pathogenesis. Therefore, the research's focus on RNA metabolism has been increasing, especially on RNA-binding proteins (RBPs). The present review summarizes RNA metabolism, exposing the different processes and the main RBPs involved. We also explore the mechanisms by which RBPs are dysregulated in PolyQ SCAs. Finally, possible therapies targeting the RNA metabolism are presented as strategies to reverse neuropathological anomalies and mitigate physical symptoms.
- Molecular hallmarks of neurodegeneration in polyglutamine spinocerebellar ataxiasPublication . Nóbrega, Clévio; Marcelo, Adriana; Vieira da Conceição, André Filipe; Encarnação Estevam, Bernardo Alexandre; Rajado, Ana Teresa; Albuquerque Andrade de Matos, Carlos Adriano; Vilhena Catarino Brito, David; Torquato Afonso, Inês; Antunes Codêsso, José Miguel; Koppenol, Rebekah; Costa, Rafael Gomes da; Afonso Reis, Ricardo António; Paulino, Rodrigo; Gomes, TiagoPolyglutamine spinocerebellar ataxias (PolyQ SCAs) comprise a group of six inherited rare neurodegenerative diseases. They are caused by abnormal mutation of a CAG tract in six otherwise unrelated genes, leading to a complex cascade of molecular events that culminate in neuronal death. Based on decades of research in these diseases, this review identifies and categorizes the distinctive hallmarks involved in the molecular pathogenesis of PolyQ SCAs. We organized these molecular signatures into three groups: (i) primary hallmarks, which directly refer to the transcription and translation of the abnormally expanded gene and protein, respectively; (ii) secondary hallmarks, which include alterations in pathways and organelles that are implicated in the disease pathogenesis; and iii) end-stage hallmarks, which highlight the final events of the pathogenesis cascade in PolyQ SCAs. This framework is expected to provide a platform for understanding the complex network of molecular mechanisms involved in these diseases and to guide current and future efforts in developing therapies.