Background: Spinocerebellar ataxias (SCAs) are a group of cerebellar diseases characterized
by progressive ataxia and cerebellar atrophy. Several forms of SCAs are caused by missense
mutations or deletions in genes related to calcium signaling in Purkinje cells. Among them, spinocerebellar
ataxia type 14 (SCA14) is caused by missense mutations in PRKCG gene which encodes
protein kinase C gamma (PKCγ). It is remarkable that in several cases in which SCA is
caused by point mutations in an individual gene, the affected genes are involved in the PKCγ signaling
pathway and calcium signaling which is not only crucial for proper Purkinje cell function but
is also involved in the control of Purkinje cell dendritic development. In this review, we will focus
on the PKCγ signaling related genes and calcium signaling related genes then discuss their role for
both Purkinje cell dendritic development and cerebellar ataxia.
Methods: Research related to SCAs and Purkinje cell dendritic development is reviewed.
Results: PKCγ dysregulation causes abnormal Purkinje cell dendritic development and SCA14.
Carbonic anhydrase related protein 8 (Car8) encoding CAR8 and Itpr1 encoding IP3R1were identified
as upregulated genes in one of SCA14 mouse model. IP3R1, CAR8 and PKCγ proteins are
strongly and specifically expressed in Purkinje cells. The common function among them is that they
are involved in the regulation of calcium homeostasis in Purkinje cells and their dysfunction causes
ataxia in mouse and human. Furthermore, disruption of intracellular calcium homeostasis caused by
mutations in some calcium channels in Purkinje cells links to abnormal Purkinje cell dendritic
development and the pathogenesis of several SCAs.
Conclusion: Once PKCγ signaling related genes and calcium signaling related genes are disturbed,
the normal dendritic development of Purkinje cells is impaired as well as the integration of signals
from other neurons, resulting in abnormal development, cerebellar dysfunction and eventually
Purkinje cell loss.