Nóbrega, ClévioMarcelo, AdrianaVieira da Conceição, André FilipeEncarnação Estevam, Bernardo AlexandreRajado, Ana TeresaAlbuquerque Andrade de Matos, Carlos AdrianoVilhena Catarino Brito, DavidTorquato Afonso, InêsAntunes Codêsso, José MiguelKoppenol, RebekahCosta, Rafael Gomes daAfonso Reis, Ricardo AntónioPaulino, RodrigoGomes, Tiago2025-12-092025-12-092025-11-102041-4889http://hdl.handle.net/10400.1/27933Polyglutamine 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.engjournal article10.1038/s41419-025-08154-2