Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias

Cerebellum. 2010 Jun;9(2):148-66. doi: 10.1007/s12311-009-0144-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis / physiology
  • Calcium / metabolism
  • Cerebellum / pathology*
  • Gene Expression Regulation / genetics
  • Humans
  • Models, Neurological
  • Nerve Degeneration / etiology*
  • Nerve Degeneration / physiopathology
  • Peptides / toxicity
  • Spinocerebellar Ataxias / complications*
  • Spinocerebellar Ataxias / genetics
  • Synaptic Transmission / physiology

Substances

  • Peptides
  • polyglutamine
  • Calcium