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.
Highlights
The cerebellum, the second largest area exceeded only by the cerebral cortex, contains more neurons than the rest of the brain
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 hypothesis that the pathogenesis of diverse spinocerebellar ataxia (SCA) is related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction
As a consequence, [Ca2+]i is remarkably increased in the presence of mutant PKCγ, thereby leading to aberrant intracellular signaling. These results indicate that an alteration in Ca2+ homeostasis and Ca2+-mediated signaling in Purkinje cells may be responsible for the neurodegeneration characteristic of Spinocerebellar ataxia type 14 (SCA14)
Summary
The cerebellum, the second largest area exceeded only by the cerebral cortex, contains more neurons than the rest of the brain. Following lesions confined to cerebellum, Schmahmann and Sherman first described a novel clinical condition characterized by an impairment of (1) executive functions, (2) spatial cognition, and (3) language [4]. This constellation of symptoms, known in humans as cerebellar cognitive-affective syndrome (CCAS), was ascribed to the functional disruption of cerebellar connections to the association cortices and limbic system [4]. 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 hypothesis that the pathogenesis of diverse SCAs is related to deranged Ca2+ homeostasis that leads to significant Purkinje cell degeneration and dysfunction
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