Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other Ataxias

Abstract

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…We observed significant and agedependent loss of firing precision of PCs in SCA2-58Q mice [91]. The reason for loss of precision firing by SCA2-58Q PCs may be due to the toxic effects of mutant ataxin-2 leading to the dysregulation of IICR [7,57,91].…”

Purkinje neuron Ca2+ influx reduction rescues ataxia in SCA28 model

“…The latter is a specific form of a cell degeneration intermediate between necrosis and apoptosis and is characterized by cell shrinkage, cytoplasm darkening, and chromatin condensation (17). In the SCA28 mouse, this phenomenon is unique, since it originates from mitochondrial dysfunction (16), while in other forms of SCA, it is associated with excitotoxicity and high levels of intracellular Ca 2+ (18)(19)(20).…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…Dantrolene was also found to be neuroprotective in a HD mouse model (YAC128) and in an SCA3 mouse model [99,100]. Dysregulated calcium signaling has emerged as a theme in many ataxias and other neurodegenerative diseases, and could provide a novel therapeutic target for RNAi therapies [101,102].…”