The Cerebellum

, Volume 9, Issue 2, pp 148–166

Cellular and Molecular Pathways Triggering Neurodegeneration in the Spinocerebellar Ataxias

  • Antoni Matilla-Dueñas
  • Ivelisse Sánchez
  • Marc Corral-Juan
  • Antoni Dávalos
  • Ramiro Alvarez
  • Pilar Latorre
Article

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.

Keywords

Spinocerebellar ataxias Cerebellum Neurodegenerative disorders Neurodegenerative mechanisms Therapy 

Abbreviations

ADCA

Autosomal dominant spinocerebellar ataxia

Ca2+

Calcium ion

CACNA1A

Calcium channel, voltage-dependent, P/Q type, alpha 1A subunit

CAG

DNA sequence coding for glutamine

CNS

Central nervous system

DRPLA

Dentatorubral-pallidoluysian atrophy

ER

Endoplasmic reticulum

FGF14

Fibroblast growth factor 14

GABA

γ-aminobutyric acid

Glu

Glutamate

HDACs

Histone deacetylases

HSP

Heat shock protein

ITPR1

Inositol 1,4,5-triphosphate receptor type 1

KCNC3

Potassium voltage-gated channel subfamily C member 3

MJD

Machado–Joseph disease

PC

Purkinje cells

PP2

Protein phosphatase 2 (formerly 2A)

PPP2R2B

Serine/threonine protein phosphatase 2 (formerly 2A) 55 kDa regulatory subunit B beta isoform

PRKCG

Protein kinase C gamma

Q

Glutamine

SCA

Spinocerebellar ataxia

SPTBN2

Beta-III spectrin

TBP

TATA-box-binding protein

UPR

Unfolded protein response

UPS

Ubiquitin-dependent proteasome system

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Antoni Matilla-Dueñas
    • 1
    • 2
  • Ivelisse Sánchez
    • 1
  • Marc Corral-Juan
    • 1
  • Antoni Dávalos
    • 1
  • Ramiro Alvarez
    • 1
  • Pilar Latorre
    • 1
  1. 1.Department of Neurosciences and Neurology Service, Health Sciences Research Institute and Hospital Germans Trias i PujolUniversitat Autònoma de BarcelonaBadalonaSpain
  2. 2.Basic, Translational and Neurogenetics Research Unit, Health Sciences Research Institute Germans Trias i Pujol (IGTP)Universitat Autònoma de BarcelonaBadalonaSpain

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