Research projects
Liquid-Liquid phase separation (LLPS) in stress and neurodegenerative diseases.
LLPS is a phenomenon in which a protein undergoes a density transition to demix from the bulk solution to form liquid droplets. In cells, many proteins, a majority of which are disordered and contain low-complexity sequences, phase separate and become a part of biomolecular condensates in the form of membraneless organelles. One such organelle formed under cell stress is ‘stress granules’ that contain several proteins and RNA. TDP-43 is one such protein that phase separates with RNA, but also forms solid amyloid aggregates in pathology. We are interested in uncovering the factors that govern the phase transitions of TDP-43 in norm and pathology.
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 Cystines (12) that form four stacked β-hairpins with axial rod-like disulfide bridges stabilizing them. 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 several neurodegenerative diseases. PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease, and frontotemporal dementia besides AD. We are interested in understanding the molecular and physiological roles of GRN in neurodegenerative diseases such as FTD.
a-Synuclein – TDP-43 heterotypic amyloids in co-morbid neurodegenerative diseases.
Many neurodegenerative proteinopathies are characterized by the deposition of misfolded protein aggregates called amyloids in neuronal and glial cells. These disorders affect diverse neuroanatomical regions in the brain and exhibit clinical heterogeneity. Although each protein aggregation disease is often presumed to be caused by misfolding of a single protein, ostensibly distinct neurodegenerative pathologies can show significant clinical and pathological overlap. It appears the phenotype variations may be attributed in part to the interactions between two or more amyloid proteins and the accumulation of biochemically distinct heterotypic protein aggregates. We are interested in the interactions between α-synuclein (αS) and transactive response DNA-binding protein 43 kDa (TDP-43), deposits of which are increasingly known to colocalize. We are specifically investigating how heterotypic amyloid aggregates play a significant role in inducing distinct phenotypes.
Design of functional amyloid and soft nanomaterials
Taking advantage of the robust thermal and enzymatic stabilities of amyloid structures, one can efficiently design synthetic amyloid materials by carefully editing their sequences. We have embarked upon such a project in which we are trying to uncover how the sequence of amyloid-forming peptides correlates with their biophysical and nanomechanical properties. Such amyloid-based nanomaterials can find their application in biotechnological and pharmaceutical industries.