Our lab’s long-standing research interests revolve around the role of environmental neurotoxic factors in the etiopathogenesis of PD and related neurodegenerative disorders. Protein aggregation and its deposits in inclusion bodies are common pathophysiological features of many neurodegenerative diseases such as PD, AD, HD and prion diseases. Our research demonstrates that exposure to environmental neurotoxic agents accelerates protein aggregation via a ubiquitin-proteasome dysfunction-dependent pathway in these disorders. We found that the neurotoxic metal manganese and the organochlorine pesticide dieldrin induce ubiquitin-proteasome dysfunction and enhance aggregation of α-synuclein protein in dopaminergic neuronal cells. Our studies also reveal that cellular prion protein binds to manganese, thereby increasing the stability of the protein, which ultimately promotes protein aggregation and neurotoxicity in neuronal cells. These studies provide new insights into the interactions between diverse environmental factors and the aggregation of neurodegenerative proteins.
Our lab has also been actively investigating the key molecular signaling events regulating dopaminergic neuronal cell death in PD. A hallmark of PD is its progressive and relatively selective loss of dopaminergic neurons in the substantia nigra pars compacta. Therefore, identifying key signaling molecules and pathways involved in this degenerative process following neurotoxic insult could provide new therapeutic approaches for treating PD. Our seminal work was the first to demonstrate that the protein kinase Cδ (PKCδ) is highly expressed in nigral dopaminergic neurons and serves as a key substrate for caspase-3 during oxidative insults leading to dopaminergic degeneration induced by Parkinsonian toxicants. We also provided the first evidence of transcriptional mechanisms underlying neuronal PKCδ expression under neurotoxic stress. These studies add new insight into molecular mechanisms underpinning oxidative damage in the neurodegenerative processes of PD and provide a basis for developing potential treatments targeting PKCδ signaling.
Our lab has also been a leader in research aimed at uncovering key upstream and downstream mediators of PKCδ signaling in dopaminergic neuronal cells. We found that the non-receptor tyrosine kinase Fyn regulates upstream signaling of the PKCδ-mediated apoptotic cell death pathway in neurotoxicity and neuroinflammatory models. We also identified a neuroprotective PKD1 kinase, which is activated by a PKCδ-dependent mechanism to protect dopaminergic neurons from the early stages of oxidative insult. These findings uncovered new therapeutic strategies to treat PD and thus have high clinical significance and therapeutic potential.
In addition to the abovementioned contributions, our lab devotes considerable effort at advancing translational research, specifically in developing new therapies targeting mitochondria and signaling molecules including PKCδ, PK2, Kv1.3 and Fyn kinase to alter degenerative processes in PD and related neurodegenerative diseases. To this synthesized novel small molecule inhibitors targeting these signaling molecules including mitochondria-targeted antioxidants for development as potential neuroprotective agents. These studies have made significant translational contributions toward identifying promising neuroprotective therapeutic targets for devastating diseases like PD. Very recently, we have established a genetically engineered L-DOPA bacterial live-therapeutic program for intervention against PD symptoms as well as a biomarker research program for the early detection of PD, AD and related disorders with funding from DOD and NIH, which have resulted in multiple publications.
Overall, his drive research projects in four major areas:
- Novel apoptotic and compensatory signaling activated during neurotoxic insult in the dopaminergic neurodegenerative process;
- Protein misfolding and neuroinflammatory mechanisms in neurotoxicity;
- Epigenetic reprogramming in neurotoxic stress; and
- Translational biomarker and drug discovery in neurotoxicity and neurodegeneration
Kanthasamy Lab in the News