Dr. Mahesh Narayan
Department of Chemistry
The work in Dr. Narayan’s laboratory focuses on mitigating oxidative stress induced by neurotoxins such as rotenone, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These neurotoxins are responsible for the generation of reactive oxygen species-related oxidative damage to protein disulfide isomerase (PDI), the chief oxidoreductase chaperone in the endoplasmic reticulum responsible for preventing neurotoxicity and accumulation of misfolded cellular debris. Reactive oxygen species (ROS) insult has been convincingly implicated in a host of pathological and behavioral changes in both neuronal (cellular) and animal models, eventually resulting in compromised or increased morbidity and mortality. Particularly, ROS-mediated accumulation of alpha-synuclein (molecular hallmark for Parkinson disease) is known to affect synaptic plasticity in the dentate gyrus and conversely, corrective transformation of ROS attenuates the deleterious role of superoxide in modulating synaptic plasticity, learning and memory.
Research Questions
- Can select carbon quantum dots (CQDs) protect PDI from becoming S-nitrosylated under nitrosative attack.
- Can select CQDs serve as prophylactics and therapeutics against loss of neuronal function and associated behavioral plasticity?
Significance of the work
Our long-term goal is to bring to clinical trials therapeutics that address neurodegeneration not only for rescuing behavioral plasticity, but also prevention of related neuropathies. It is our vision that someday potent ethnopharma-based neurodegeneration preventatives can be incorporated into processed foods and “vaccinate” populations from early childhood. The benefits of our approach are: 1) The research thrust is both preventative and therapeutic and can be used to target populations over a wide age, gender and ethnic spectrum (2) CQDs have gained attention owing to their high aqueous solubility, non-toxicity, biocompatibility, bioimaging and resistance to photobleaching (3) surface-functionalized CQDs lacks adverse side-effects associated with chemotherapeutics.
Methods to be learned
Dr. Narayan’s laboratory uses analytical and biochemical methods in their approach. Students will develop and characterize select CQDs as potent NOx scavengers, use molecular recognition and then target validation using in vitro assays.
Participants will initiate work to establish the ROS-scavenging (prophylactic approach) and fibril dissolving (therapeutic approach) ability of select surface-functionalized CQDs. The anti-ROS activity will be determined using model NOx generators routinely employed by Dr. Narayan’s Laboratory. Further, fibril dissolving ability will be determined using ThT assay and other analytical methods such Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM). Moreover, mass spectrometric analysis will aid in determining the identity of the radical-scavenged products, if any. Successful radical scavengers and anti-fibrillizing agents will then be introduced into a human derived neuroblastoma cell line (SH-SY5Y), prior to oxidative insult of the cells using different neurotoxins such as rotenone, 6-OHDA and MPTP. Neuronal integrity against debris accumulation, a key biomarker for eventual compromised neuronal plasticity, will be monitored using green fluorescent protein tagged synphilin-1 through fluorescence microscopy.