Prof. Dr. Lawrence Rajendran

 

Main Goals

The Systems and Cell Biology of Neurodegeneration Lab, at the Department of Psychiatry Research, studies the molecular and cellular basis of neurodegenerative diseases.

Keywords

Alzheimer’s disease, membrane trafficking, endocytosis, amyloid, systems biology

Group members

1 Professor, 1 Lab Manager, 3 PhD Students, 1 Postdoc

Previous and Current Research

Systems Biology: In this part, we investigate the etiology of Alzheimer Disease. There are thousands of coding and non-coding genes in the human genome. How do these contribute to the pathogenesis? Neurodegenerative diseases are complex whose etiologies cannot be pinned to a few genes. Particularly, in the case of late onset Alzheimer’s disease (AD) that comprises more than 95% of the AD population, the identity of the risk genes is still not known. By combining functional genomics with computational tools, we intend to understand the complex molecular network that underlies AD. We used state of the art high-throughput screening methods to identify genes involved in Alzheimer’s disease and by performing network analysis on the identified genes, we have zeroed in on certain key regulators. Further characterization in vitro and in vivo revealed novel insights into the pathology. We are now investigating the molecular mechanisms of the other hits that were identified by this screen.

Cell Biology: On the cell biology aspect, our lab investigates the possible physiological roles of proteins involved in the onset of Alzheimer’s disease. We address an important question relating to the disease: Is Alzheimer’s disease a physiological process gone awry? We study the role of membrane trafficking and subcellular compartmentalization in amyloid plaque formation and synaptic dysfunction observed in Alzheimer’s disease.

Future Projects

Our goal is to understand the molecular complexity underlying Alzheimer’s disease. Not only do we intend to draw a “parts list” identifying components but also in parallel, characterize the mechanism by which these components regulate this process. Such systems biology approaches would not only advance our understanding of the disease but also would aid in the development of therapeutics and diagnostics and in providing biomarkers for personalized medicine. We are now extending our screening approaches to various other neurodegenerative diseases to find the commonality and specificity in these diseases.
Our investigations into the cell biology of the disease would help curate a roadmap wherein the relevant players of the disease are placed in a cellular context. Does the disease pathway hijack existing cellular machinery for its pathogenesis or is the disease a physiological process gone awry? How does aging affect membrane trafficking, lipid homeostasis, cellular signaling that could potentiate the onset of the disease? By understanding the cell biology of the disease, could we identify better biomarkers or design better inhibitors? Our projects are aimed at addressing these questions.

Techniques and Equipment

Cell biology techniques (immunostaining, endocytosis, pulse-chase, preparation of exosomes, lipid rafts, subcellular trafficking, targeting, BAC technology, RNAi (si and esiRNAs, protease assays, standard biochemistry, molecular and cell biology techniques, etc)
Screening approaches include use of RNAi screens, small molecule compound screens, computational network analysis, medium to highthroughput liquid handling and assay systems, etc)

Selected Publications

• Rajendran, L., Knölker, H.J., Simons, K. Subcellular targeting strategies for drug design and delivery. Nat Rev Drug Discov. Jan; 9(1): 29-42 (2010).
• Aguzzi, A., Rajendran, L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron. Dec 24; 64(6): 783-90 (2009).
• Rajendran, L., Schneider, A., Schlechtingen, G., Weidlich, S., Ries, J., Braxmeier, T., Schwille, P., Schulz, J., Schroeder, C., Simons, M., Jennings, G., Knoelker, H.-J., Simons, K. Efficient inhibition of the Alzheimer’s disease β-secretase by membrane targeting. Science Apr 25: 320(5875): 520-3 (2008).

Funding

Velux Stiftung, NCCR Neural Plasticity and Repair, Alzheimer Research Initiative, Hans- & Ilse Breuer Stiftung, SNF.