ABC-RI
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Àcerca do Centro de Investigação Biomédica do Algarve => ABC-RI
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Percorrer ABC-RI por autor "Afonso Reis, Ricardo António"
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- Insights into cockayne syndrome type B: what underlies its pathogenesis?Publication . Afonso Reis, Ricardo António; Madeira, Cristiana; Vilhena Catarino Brito, David; Nóbrega, ClévioCockayne Syndrome (CS) is an autosomal recessive disorder arising from mutations in either of two disease-associated genes, ERCC6 or ERCC8. CS patients exhibit cutaneous photosensitivity, neuropathological abnormalities, severe growth retardation, a distinctive facial appearance with pronounced sunken eyes, musculoskeletal anomalies, sensory impairment, and dental decay. Approximately 70% of all CS cases carry ERCC6 mutations; therefore, this review will focus solely on Cockayne Syndrome complementation group B (CS-B). CS-B exhibits several hallmarks of aging, including genomic instability, epigenetic modifications, loss of proteostasis, and mitochondrial failure. CS-B is proposed to result from the accumulation of DNA damage and the resulting transcription impairment. However, the main pathophysiological mechanisms underlying the severe cellular impairments observed in CS-B remain unclear. Here, we review the current literature to elucidate ERCC6-related mechanisms, highlighting the key and emerging pathological mechanisms underlying CS-B, as well as their putative interactions. Considering the mechanisms that heavily rely on ERCC6, we propose that CS-B pathogenesis arises from a combination of DNA damage accumulation, transcriptional dysregulation, and mitochondrial dysfunction. Furthermore, we argue that these molecular features influence each other, rather than acting as isolated mechanisms. This suggests that the crosstalk between mechanisms is a key factor for CS-B pathogenesis. Although efforts have been made to unveil CS-B pathogenesis, research is still lacking, hindering progress in understanding this deadly disease. Future work will prove crucial to determine the main contributor to CS-B pathogenesis and identify new interactions between CS-B-affected mechanisms.
- 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.