title: Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias.
abstract: The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. To date, more than 30 genes have been identified triggering the well-described clinical and pathological phenotype, but the underlying cellular and molecular events are still poorly understood. Studies of the functions of the proteins implicated in SCAs and the corresponding altered cellular pathways point to major aetiological roles for defects in transcriptional regulation, protein aggregation and clearance, alterations of calcium homeostasis, and activation of pro-apoptotic routes among others, all leading to synaptic neurotransmission deficits, spinocerebellar dysfunction, and, ultimately, neuronal demise. However, more mechanistic and detailed insights are emerging on these molecular routes. The growing understanding of how dysregulation of these pathways trigger the onset of symptoms and mediate disease progression is leading to the identification of conserved molecular targets influencing the critical pathways in pathogenesis that will serve as effective therapeutic strategies in vivo, which may prove beneficial in the treatment of SCAs. Herein, we review the latest evidence for the proposed cellular and molecular processes to the pathogenesis of dominantly inherited spinocerebellar ataxias and the ongoing therapeutic strategies.
authors.affiliation: Department of Neurosciences and Neurology Service, Health Sciences Research Institute and Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. amatilla.igtp.germanstrias@gencat.cat
authors.forename: Antoni
authors.initials: A
authors.lastname: Matilla-Dueñas
authors.forename: Ivelisse
authors.initials: I
authors.lastname: Sánchez
authors.forename: Marc
authors.initials: M
authors.lastname: Corral-Juan
authors.forename: Antoni
authors.initials: A
authors.lastname: Dávalos
authors.forename: Ramiro
authors.initials: R
authors.lastname: Alvarez
authors.forename: Pilar
authors.initials: P
authors.lastname: Latorre
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000209:etiology* / Q000503:physiopathology; D010455:Peptides / Q000633:toxicity; D020754:Spinocerebellar Ataxias / Q000150:complications* / Q000235:genetics; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D010455:Peptides; C097188:polyglutamine; D002118:Calcium