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- From the molecular hallmarks to motor behavior: characterization of a new transgenic mouse model for spinocerebellar ataxia type 2Publication . Afonso, Inês T.; Koppenol, Rebekah; Conceição, André; Paulino, Rodrigo; Mirapalheta, Lourenzo; Matos, Carlos A; Nóbrega, ClévioSpinocerebellar ataxia type 2 (SCA2) is a rare disease with no cure, and therefore patients depend on symptomatic and supportive treatments. It is a highly debilitating disease affecting predominantly the brain with symptoms that include motor and coordination impairment. SCA2 is caused by an abnormal expansion of the CAG triplet in the coding region of the ATXN2 gene. When it has above 33 CAG repeats, it originates a protein with an abnormally expanded glutamine tract. The mutant protein impairs several cellular functions, leading to neuronal degeneration and death. Several rodent models were developed to study the neuropathology and potential therapies for SCA2. However, most of them fail to mimic a complete SCA2 phenotype, taking too long to develop diseaserelated symptoms or failing to display neuronal-associated deficits.
- 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.