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.

Glutamate Receptor δ2 Associates with Metabotropic Glutamate Receptor 1 (mGluR1), Protein Kinase Cγ, and Canonical Transient Receptor Potential 3 and Regulates mGluR1-Mediated Synaptic Transmission in Cerebellar Purkinje Neurons

“…Although the C1 domain mutants display kinase activity, they are unable to phosphorylate and thereby inactivate TRPC channels in vivo (Adachi et al, 2008). This failure to phosphorylate TRPC3 channels alters Ca 2ϩ homeostasis, which likely contributes to neurodegeneration (Matilla-Dueñas et al, 2010). This fits with the progressive Purkinje cell loss in moonwalker mice whose TRPC3 channel is mutated such that cannot be phosphorylated and inactivated by PKC␥ (Becker et al, 2009).…”

Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19

“…1 The remaining known SCA types are caused by missense mutations or chromosomal rearrangements (SCA5, 11, 13-15, 20, 23, 27, 28, 31, and 35) in genes displaying a wide range of protein functions, often causing alterations in synaptic transmission via calcium, potassium, and glutamate signaling. 1,[5][6][7] We previously mapped SCA19 in a large Dutch family (4 generations with 13 affected members) to a region of approximately 38 Mb located in chromosomal region 1p21-q21. 8 The SCA19 locus shows significant overlap with the SCA22 locus later reported in a single Chinese family, 9 suggesting that SCA19 and SCA22 might be caused by mutations in the same gene and lead to an ataxia type with a worldwide distribution.…”

Neurochemistry and Neuropharmacology of the Cerebellar Ataxias

“…However, as this is not possible in most cases, neurochemical evidence might provide useful clues in the search for therapeutic remedies (171,172). The study of animal and experimental models of disease, the use of precise methods for the measurement of ataxia (clinical semiquantitative scales, quantitative movement analysis, etc) and the recruitment of homogenous study populations (22), are all highly recommended.…”