Research projects
Biomolecular Condensates in stress and neurodegenerative diseases.
LLPS is a phenomenon in which a protein undergoes a density transition, demixing from the bulk solution to form liquid droplets. In cells, many proteins, most of which are disordered and contain low-complexity sequences, phase separate and form biomolecular condensates as 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 aim to uncover the factors that govern TDP-43 phase transitions in health and disease.
Granulins 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.
Heterotypic amyloids in 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 brain regions and exhibit clinical heterogeneity. Although each protein aggregation disease is often presumed to result from misfolding of a single protein, ostensibly distinct neurodegenerative pathologies can show significant clinical and pathological overlap. Phenotypic variation may be attributed in part to 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), Tau, 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
By leveraging the robust thermal and enzymatic stability of amyloid structures, we can efficiently design synthetic amyloid materials through careful sequence editing. We have embarked on a project to uncover how the sequence of amyloid-forming peptides correlates with their biophysical and nanomechanical properties. We are also interested in developing redox-sensitive viscoelastic protein-based viscoelastic materials. Such soft materials can be applied in the biotechnology and pharmaceutical industries.