Consequences of protein (mis)folding
  • How and why some (mis)folded proteins promote proteotoxicity (and some not)!!
  • What happens to proteins during aging!!
Cancer, diabetes, cardio-vascular diseases and several neurodegenerative disorders represent the majority of the protein-(mis)folding related health-setbacks in the aging population. For example, in each of the neurodegenerative disorders known, a “metastable-protein” (mis)folds and damages the protein-homeostasis (proteostasis) in the nerve cells. Formation of toxic aggregates by the (mis)folded islet amyloid polypeptide (IAPP) contributes to ß-cell dysfunction and diabetes. Soluble pre-amyloid oligomers of (mis)folded proteins are present in the cardiomyocytes of many human heart failure samples. Chronic, uncontrolled protein (mis)folding and resultant abnormal heat shock protein load is known to foster tumor development. Importantly, loss-of-function of these (mis)folded proteins is not likely to be the major reason behind proteotoxicity. Rather, these (mis)folding of these proteins disturb several common protein-metabolic pathways (starting from protein synthesis, folding, transport to degradation) resulting in disease-conditions. This common pathogenic modality offers unique opportunity to discover novel drug-targets that could be useful in ameliorating multiple proteotoxic conditions; however, systemic investigations are emergent.

In our lab, we are interested in studying the impact of “one” (mis)folding-prone protein on the cellular proteome using different protein-(mis)folding disease models. The novelty of our approach relies on the identification of exclusive molecular players which could be targeted in multiple diseases. Currently, we are using mutant versions of a-synuclein (responsible for familial Parkinson’s disease), Ubiquilin – 2 (Amyotrophic Lateral Sclerosis), Huntingtin (Huntington's disease) and a proteostasis-sensor protein FlucDM-EGFP as model (mis)folding-prone proteins. Several cell-lines conditionally expressing these (mis)folding-prone proteins have been generated. Multiple chemical biology tools and quantitative proteomics protocols to study the proteostasis changes in these cell-lines have been standardized. Pilot experiments to study the impact of protein-(mis)folding on the soluble and functional proteome, activation of stress response and protein degradation etc. have been initiated. These investigations promise to:
  • understand the mechanism of proteotoxicity in protein-(mis)folding diseases!!
  • identify novel drug targets!!
  • develop multi-dimensional, high-throughput small-molecule screening platforms for protein-(mis)folding diseases!!
Major focus areas
  • Changes in proteome with age
  • Membrane proteins and stress signalling
  • Proteostasis signalling
Current projects
  • Protein homeostasis in aging and age-related diseases – a systemic approach

  • Activities

    1. Systemic study to define the reasons for decline in protein homeostasis in mammalian aging
    2. Systemic study to define the reasons for proteostasis insufficiency in neurodegenerative disease models
    3. Monitoring the aggregation of model proteostasis dependent metastable proteins in neurodegenerative disease models
    4. Interactome of proteostasis sensor proteins in neurodegenerative disease models
    5. Interactome of age-related neurodegenerative disease proteins in presence of proteostasis sensor proteins

  • Role of cellular membranes in stress signalling and protein homeostasis maintenance

  • Activities

    1. To establish a model to investigate how membrane-related processes are implicated in stress sensing and proteostasis maintenance, particularly during aging.
    2. To define changes in the cell and nuclear membrane proteome and their effects on signalling during stress and aging.
    3. To define changes in cell and nuclear membrane composition and function in cell culture models of age-related neurodegenerative diseases.
    4. To measure the efficiency of nucleo-cytoplasmic transport during stress and aging.
    5. To study the mechanistic details of the involvement of candidate membrane proteins in stress signalling.
Research collaboration
  • Prof. F. Ulrich Hartl, Max Planck Institute of Biochemistry, Martinsried, Germany
  • Prof. Nitai P. Bhattacharyya and Dr. Debashis Mukhopadhayay, Saha Institute of Nuclear Physics, Bidhannagar, West Bengal
  • Dr. Malay Bhattacharyya, Indian Institute of Engineering Science and Technology, Shibpur, West Bengal
  • Prof. Nihar Ranjan Jana, National Brain Research Centre, Manesar, Haryana
  • Prof. Subhasis Mukherjee, Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, West Bengal

    Copyright (C) 2014, Swasti Raychaudhuri. All rights reserved.