Associate Professor of Biophysical Chemistry
- B.Sc & M.Sc; Delhi University, India (1996).
- Ph.D; All India Institute of Medical Sciences, New Delhi, India (2000).
- I Post-doc; Florida State University, FL (2001-2004)
- II Post-doc; Mayo Clinic, FL (2004-2006)
- Assistant professor; Mayo Clinic, FL (2006-2008).
- Protein misfolding in neurodegenerative diseases.
- Biophysics of amyloid aggregation in Alzheimer’s & Parkinson’s diseases.
- Rational, structure based drug designs.
- Use of traditional medicines in drug design.
Our research falls in the broad field of biological chemistry with a major focus on biophysics of proteins and peptides. We are currently focused on understanding several different aspects of amyloid-β (Aβ) peptide aggregation involved in Alzheimer’s disease (AD), mainly via biophysical and chemical biology approaches.
We are also interested in developing rationally-designed molecules that can inhibit the formation of amyloid aggregates and prevent aberrant protein aggregation.
Protein misfolding and amyloidogenesis in neurodegenerative diseases.
The underlying biochemical commonality among many neurodegenerative diseases including Alzheimer’s and Parkinson’s disease (PD) is that they all involve proteins that undergo misfolding and subsequent aggregation to form ‘amyloids’. These amyloid aggregates are widely believed to be neurotoxic and responsible for neurodegeneration in the brain. Monomeric Aβ is natively unstructured and self-associates to large fibrillar aggregates that eventually deposit as amyloid plaques. Although ambiguity remains over the toxic species in the aggregation pathway, many evidence suggests soluble aggregates of low-molecular weight, commonly referred as ‘soluble oligomers’, are highly toxic to the neuronal cells. It is very important to elucidate whether the oligomers that are toxic to the neuronal cells are ‘on pathway’ or ‘off pathway’ products in the aggregation pathway. In our lab, we are interested in understanding the molecular mechanisms and structural changes that take place during the early steps of Aβ aggregation; generating, isolating and elucidating the molecular structure stable, homogeneous soluble Aβ oligomers; examining the effects of various fatty acids and other lipids on Aβ aggregation besides others. Collaboratively, we are looking at the stochastic modeling the se processes.
Rational, Structure-based designs of therapeutic molecules.
We interested in designing molecules that can interact with Aβ or a-syn (in PD) in a specific manner to inhibit this process. Since formation of ‘cross b-sheet’ structure is an underlying paradigm for many ‘amyloid’ diseases, the ultimate goal is to explore the possibility of promiscuous molecules that can effectively inhibit the formation of cross β-sheet aggregates irrespective of the polypeptide sequence. We approach this aim from a chemical biology perspective by taking advantage of the reactivity of Ab for ligand and building an inhibitor around it, testing its effectiveness in vitro and in vivo. Our research is highly interdisciplinary involving a collaborative effort from other laboratories whose expertise might provide answers to some of our research objectives.
Role of Granulins (Epithelins) in neurodegenerative diseases.
Granulins (Grn) (also called epithelins) are small proteins of about 6 kDa that are derived from a larger precursor protein called progranulin (Pgrn), of approximately 540 aa. Both Grn and Pgrn are found to modulate cell growth. Each Pgrn contains a secretory signal sequence and 7.5 repeats of the 12-Cys Grn motifs. Grn is characterized by highly conserved 12-Cys motifs that form a novel structural architecture of four stacked β-hairpins with an axial rod of disulphide bridges and with the peptide chain twisting through a left-handed super helix. Although the family of these peptides is well understood to be involved in tissue development and wound repair, they have recently been implicated as a risk-factor in Alzheimer’s disease. In fact, the Prgn expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and frontotemporal dementia besides AD. It is hypothesized that there could be interaction between tau, a protein responsible for the formation of neurofibrillary tangles in AD. Despite its implication in AD, the possible interaction between Aβ and Grn has not been investigated. Interestingly, the novel fold of Grn is strikingly similar to Aβ fibril cross β-sheet topology and some β-strands of Grn are potentially compatible to interact with the C-terminal part of Aβ. Therefore, we are interested in understanding the molecular and physiological roles of Grn in AD and its interaction with Aβ. Specifically, I would like to investigate whether Grn can nucleate Aβaggregation by forming a structural template and extend my research in understanding similar effects on other neurodegenerative diseases.
- Srisairam Achuthan, Bong Jae Chung, Preetam Ghosh, Vijayaraghavan Rangachari and Ashwin Vaidya. A Modified Stokes-Einstein Equation for AβAggregation. (2011) BMC Bioinformatics (in press).
- Amit Kumar, Rebekah Rice, Lea Paslay, Dipti Singh, Pritesh Patel, Ewa Bienkiewicz, Sara Morgan and Vijayaraghavan Rangachari. Non-esterifed fatty acids generate distinct Amyloid-b (Ab42) oligomers via pathway distinct from Fibril Formation. (2011) PLoS One April 19, 6(4), e18759.
- Amit Kumar, LaMaryet Moody, Jason Olaivar, Nerissa Lewis, Rahul Khade, Alvin Holder, Yong Zhang and Vijayaraghavan Rangachari. Inhibition of Ab42 peptide aggregation by a mixed–metal binuclear ruthenium(II)-platinum(II) complex: Potential for multi-metal organometallics as anti-amyloid agents. (2010). ACS Chemical Neuroscience 1, 691-701.
- Preetam Ghosh, Amit Kumar, Bhaswati Datta, and Vijayaraghavan Rangachari. Dynamics of Protofibril Elongation and Association involved in Aβ42 Peptide Aggregation in Alzheimer’s Disease. (2010). BMC Bioinformatics 11(Suppl 6): S24.
- Brenda D. Moore, Vijayaraghavan Rangachari, William M. Tay, Nicole M. Milkovic, and Terrone L. Rosenberry. Covalent Cross-Linking of Ab(1-42) in vitro is Accelerated in Fibrils and Oligomers Relative to Monomers. (2009).Biochemistry 48, 11796-11806.
- Vijayaraghavan Rangachari, Brent Healy, Brenda D. Moore, Leilani Sonoda, Bernadette Cusack, Abdul Fauq and Terrone L Rosenberry. Rationally designed dehydroalanine (DAla) containing peptides inhibit amyloid-b (Ab) aggregation and effect fibril disassembly. (2009) Biopolymers 91(6), 456-465.
- Thomas L. Kukar, Thomas B. Ladd, Maralyssa A. Bann, Patrick C. Fraering, Rajeshwar Narlawar, Alfred Welzel, Robert W. Price, Ghulam M. Maharvi, Brenda Moore, Vijayaraghavan Rangachari, Bernadette Cusak, Brent Healy, Jason Eriksen, Karen Jansen-West, Christophe Verbeeck, Debra Yager, Christopher Eckman, Robert Chapman, Boris Schmidt, Dominic Walsh,Wenjuan Ye, Michael S. Wolfe, Sarah Sagi, Barbara A. Cottrell, Justin Torpey,Edward H. Koo, Terrone L. Rosenberry, Abdul Fauq, Todd E. Golde. Substrate targeting g-Secretase Modulators. (2008) Nature 453, 925-930.
- Jungsu Kim, Fanggeng Zou, Victor M. Miller, Yona Levites, Karen Jansen West, Craig W. Zwizinski, Brenda D. Moore, Fredrick J. Troendle, Maralyssa Bann, Christophe Verbeeck, Robert W. Price, Lisa Smithson, Vijayaraghavan Rangachari, Leilani Sonoda, Kayleigh Wagg, Li Ma, David Cangemi, Samuel G. Younkin, V. Shane Pankratz, Ronald C. Petersen, Neil R. Graff-Radford, Dennis W. Dickson, Terrone Rosenberry, Steven G. Younkin, Todd E. Golde. BRI2 (ITM2B) Inhibits Ab Deposition in Vivo and Shows Genetic Association with Alzheimer’s Disease. (2008) J. Neuroscience 28 (23), 6030-6036.