Disrupted Calcium Signaling in Animal Models of Human Spinocerebellar Ataxia (SCA)

Abstract

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 40 autosomal-dominant genetic and neurodegenerative diseases characterized by loss of balance and motor coordination due to dysfunction of the cerebellum and its efferent connections. Despite a well-described clinical and pathological phenotype, the molecular and cellular events that underlie neurodegeneration are still poorly undaerstood. Emerging research suggests 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. Ca²⁺ signaling in Purkinje cells is important for normal cellular function as these neurons express a variety of Ca²⁺ channels, Ca2+-dependent kinases and phosphatases, and Ca²⁺-binding proteins to tightly maintain Ca²⁺ homeostasis and regulate physiological Ca²⁺-dependent processes. Abnormal Ca²⁺ levels can activate toxic cascades leading to characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells via inhibitory signals; thus, Purkinje cell dysfunction or degeneration would partially or completely impair the cerebellar output in SCAs. In the absence of the inhibitory signal emanating from Purkinje cells, DCN will become more excitable, thereby affecting the motor areas receiving DCN input and resulting in uncoordinated movements. An outstanding advantage in studying the pathogenesis of SCAs is represented by the availability of a large number of animal models which mimic the phenotype observed in humans. By mainly focusing on mouse models displaying mutations or deletions in genes which encode for Ca²⁺ signaling-related proteins, in this review we will discuss the several pathogenic mechanisms related to deranged Ca²⁺ homeostasis that leads to significant Purkinje cell degeneration and dysfunction.

Keywords: Ca2+ signaling; Purkinje cells; spinocerebellar ataxias.

Figure 1

Lurcher δ2 glutamate (GluD2)-induced cell death. Lurcher GluD2 receptors show constitutive and continuous influx of Na⁺ and Ca²⁺. Intracellular ATP levels are decreased probably by overactivation of the Na⁺/K⁺-ATPase. Compromised ionic homeostasis together with decreased ATP levels can lead to cell swelling and subsequent cell death. Secondary Ca²⁺ influx through voltage-gated Ca²⁺ channels (VGCCs) could activate a variety of Ca²⁺-dependent enzymes, such as calpains, and potentially contribute to Purkinje cell death through different pathways. Modified from [100].

Figure 2

Subtype I metabotropic glutamate receptors-Transient Receptor Potential Canonical 3 (TRPC3)-PKCγ (mGluR1-TRPC3-PKCγ) signaling at Purkinje cell synapse. TRPC3 channels and PKCγ primarily respond to phospholipase C (PLC)-coupled receptors, such as mGluR1. TRPC3 channel activity is negatively regulated through phosphorylation by PKCγ. When stimulated, mGluR1 activates phospholipase C (PLC) which hydrolizes phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). Subsequently, the endoplasmic reticulum (ER)-Ca²⁺ store depletion by IP₃ activates the ER Ca²⁺-sensor STIM1 which interacts with and activates TRPC3 channels. In addition, DAG has profound effects on the TRPC3 channels through PKC but it can also activate TRPC3 channels in a non-PKC-dependent manner. In turn, DAG formation is also promoted by mGluR1-dependent activation of phospholipase D (PLD) through the small GTP-binding protein Rho. In addition, mGluR1 activation triggers the opening of GluD2 receptors. Modified from [121].

Figure 3

The IP₃ receptor type 1 (IP₃R1)-mutant Atxn2 interaction-induced cell death. The IP₃R1–mutant ataxin-2 (Atxn2) interaction results in increased IP₃R1 activity. The abnormal Ca²⁺ signaling determines mitochondrial Ca²⁺ overload, release of cytochrome C and, consequently, induction of Purkinje cell death via dark cell degeneration (DCD). Modified from [22].