FIGURE 1.

A proposed regulatory model of mutant PKCγ, translocation in the SCA14-associated Purkinje cells of the cerebellum. This is a two-compartment model where one compartment is cytosol, whereas the other compartment is plasma membrane. This model provides the mechanistic basis of how the translocation of mutant PKCγ and DGKγ molecules could be regulated in SCA14 disease. This model suggests that in diseases associated with cPCs, the mutant PKCγ is constitutively active and resides in the cytosol. In turn, this constitutively active molecule induces the phosphorylation and activation of the cytosolic DGKγ molecule even during the basal or unstimulated conditions. In contrast, to the wild-type model, the current model suggests that both PKCγ and DGKγ are active and cytosolic even during basal conditions. Depolarization-induced activation of purinergic receptor leads to the local generation of DAG and, in turn, induces the translocation of both mutant PKCγ and DGKγ from cytosol to membrane. Once in the plasma membrane compartment, the already active DGKγ molecule directly converts DAG to PA through DAG phosphorylation.