Protein Kinase C Delta (PKCδ) and Parkinson's Disease
Understanding the PKC family of kinases
Kinases play a key role in regulating most cellular pathways in the human body. Kinases regulate the activity of cellular proteins through a process called phosphorylation. A specific class of kinases called Protein kinase C (PKC) plays a critical role in a number of functions including the cell growth, proliferation, survival, trafficking, differentiation, secretion, and in programmed cell death. While these processes are important for the health of normal cells, inappropriate activation contributes to the development and progression of cell death and neurodegenerative disorders.
All PKC proteins consist of the regulatory domain (N-terminus) and the catalytic domain(C-terminus). There are 12 PKC isoforms and are classified into three distinct subfamily groups based on their activation patterns.
Conventional PKC (cPKC): Requires both phospholipids and calcium for activation.
Novel PKC (nPKC) isoforms: Requires phospholipid but not calcium for activation.
Atypical PKC (aPKC) isoforms: Requires neither calcium nor phospholipids for activation.
Protein kinase Cd (PKCδ) is a member of the nPKC family. PKCδ has been implicated in cell differentiation, proliferation and programmed cell death. PKCδ can be activated by 1) translocation, 2) phosphorylation, and 3) caspase-3 dependent proteolytic cleavage. The mode of PKCδ activation depends on the cell type and stimuli.
Establishing PKCδ as a potential therapeutic target in PD
In the past decade, we have discovered protein kinase C delta (PKCδ) as an oxidative stress-sensitive kinase, which functions as a key mediator and amplifier of apoptotic cell death in PD.
Oxidative insult persistently activates PKCδ by proteolysis via caspase-3 dependent cleavage in dopaminergic neurons in cell culture and animal models of PD. High levels of PKCδ protein expression is observed in nigral dopaminergic neurons compared to striatum and other brain regions. PKCδ inhibitor rottlerin offered excellent neuroprotective effect in both cell culture and animal models of PD. PKCδ knockout animals are resistant to MPTP-induced dopaminergic degeneration.
Development of novel neuroprotective agents targeted against PKCδ in PD
We have developed translational PD therapeutic strategies targeting the proapoptotic PKCδ cell death signaling pathway. Our translational research is based on solid mechanistic studies aimed at determining the PKCδ as therapeutic target for PD, and, to our knowledge, we are the only group focusing on this kinase for neuroprotective treatment in PD.
We used multi-tier screening approach, which helped us to identify lead PK 100 series analogs with excellent neuroprotective activity in cell culture and animal models of PD. The new analogs are highly potent and do not show any notable off-target effects. Preclinical efficacy studies indicate lead PK compounds were neuroprotective in animal MPTP PD model. Early results indicate these novel compounds interrupt the PD mechanisms, rather than just treat disease symptoms.
PK neuroprotective technology was reviewed and ranked among top neuroprotective approaches by Foresight Science &Technology™ Company, initiated by NIH.
PK Biosciences is dedicated to developing innovative medicines for neuroinflammatory and neurodegenerative disorders. The company’s proprietary small molecule inhibitor compounds are derived from natural products.PK Biosciences has a portfolio of proprietary compounds selectively targeting cell death signaling molecules implicated in neuroinflammation and neurodegeneration.
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