AUTHOR=Aslam Naveed , Alvi Farah 

TITLE=Simplified Model of PKCγ Signaling Dysregulation and Cytosol-to-Membrane Translocation Kinetics During Neurodegenerative Spinocerebellar Ataxia Type 14 (SCA14)

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 13 - 2019

YEAR=2020

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2019.01397

DOI=10.3389/fnins.2019.01397

ISSN=1662-453X

ABSTRACT=Spinocerebellar ataxia type 14 (SCA14) is an autosomal neurodegeneration disease clinically characterized by progressive ataxia in the patient’s gait, accompanied by slurred speech and abnormal eye movements. These symptoms are linked to the loss of Purkinje cells, which leads to cerebellar neurodegeneration. Purkinje cell observations link PKCγ to SCA14. Observations also show that link between PKCγ and SCA14 relies on a gain-of-function mechanism, and, in fact, both positive and negative regulation of PKCγ expression and activity may result in changes in cellular number, size, and complexity of the dendritic arbors in Purkinje cells. Here, we investigate a key question relating to this system: why is PKCγ membrane residence time reduced in SCA14 mutant cPCs compared to wild-type (WT) cPCs? In this study, we investigate this question through two contrasting PKCγ signaling models in cPCs. The first model proposed in this study describes the mechanism through which PKCγ signaling activity may be regulated in WT cPCs. In contrast, the second model explores how mutations in PKCγ signaling affect the state of SCA14 in cPCs. Both models show that, in response to extracellular stimuli-induced depolarization of the membrane compartment, PKCγ and DGKγ translocate to the membrane. Our results also indicate that, for the same set of parameters, PKCγ membrane residence time is shorter in the SCA14 mutant model compared to the WT model. These results show how PKCγ membrane residence time is regulated by DAG, causing translocated PKCγ to return to the cytosol as DAG levels drop. This study shows that, when the strength of the extracellular signal is held constant, the membrane lifetime of mutant PKCγ is reduced. This reduction is due to the presence of constitutively active mutant PKCγ in the cytosol. Cytosolic PKCγ, in turn, leads to phosphorylation and activation of DGKγ while it is still residing in the cytosol. This effect occurs even during the resting conditions. Thus, the SCA14 mutant model explains that, when both DAG effector molecules are active in the cytosol, their interactions in the membrane compartment are reduced, critically influencing PKCγ membrane residence time.