Aging-associated diseases (e.g. neurodegeneration, declines in muscle function, etc.) pose a major societal and economic burden and impart a devastating impact on patients and their family caretakers. These diseases are hallmarked by a progressive failure of cellular maintenance mechanisms that control pathological protein misfolding and aggregation. In our lab, we are interested in 1) the impact of protein AMPylation, a novel post-translational modification, 2) the post-translational regulation of Hsp70 family chaperones in neurodegeneration and aging, 3) the regulation of protein aggregation processes, and 4) the redundancy / diversity amongst Hsp70 family chaperones. We are also engaged in the development of heavy-chain only "nanobodies" to characterize and manipulate specific components of the proteostasis machinery both in vitro and in vivo.
Proteostasis in health & disease
Proteostasis is the orchestration of numerous pathways which regulate the production, conformation, interactions, and clearance of individual proteins within a cell. As we age, the efficacy of our proteostasis machinery declines, resulting in increased incidences of protein misfolding and aggregate formation. This process is inherent to neurodegenerative diseases, which are characterized by the misfolding and accumulation of distinct protein aggregates. Our lab is interested in uncovering novel methods of proteostasis control and deciphering how, when, and why disease-linked protein species aggregate in cells.
Post-translational regulation of chaperone activity
Eukaryotic cells have evolved elaborate mechanisms which regulate the processes of protein translation, folding, and degradation - a global cellular program termed "proteostasis" (see above). Molecular chaperones, such as those in the heat shock protein (HSP) family, assist in proper protein folding and are a critical component of the cell's proteostasis machinery. Yet, beyond transcription, the intracellular regulation of HSPs remains poorly understood. Given their abundance and critical role in protein folding, the reversible regulation of HSPs by post-translational modifications (PTMs) has recently emerged as a novel avenue of study.
Alongside more well-known PTMs such as phosphorylation, we are particularly interested in AMPylation, a novel PTM which negatively regulates the ER-resident HSP70 family chaperone BiP through attachment of an AMP to Ser/Thr residues (Left). This process is catalyzed by conserved enzymes ("AMPylases") present as a single copy in most metazoans (e.g. FIC-1 in C. elegans, mFICD in mice, and HYPE in humans). Recently, our lab and others have uncovered a role for AMPylation in modulating the aggregation dynamics and toxicity of a number of ND-associated proteins.
We aim to investigate how PTMs, such as phosphorylation or AMPylation, control HSP function in health and disease. We use complementary in vitro and in vivo models to study how post-translational HSP modifications alter protein aggregation dynamics. C. elegans models are used to test novel concepts of HSP regulation and to investigate how HSPs affect protein aggregation. Our research will yield new mechanistic insights into the relationship between PTMs and protein aggregation.
The molecular basis of polyglutamine (polyQ) repeat aggregation
We are interested in investigating neurodegenerative polyQ repeat disorders such as Huntington’s disease and sporadic cerebellar ataxias. We aim to decipher how, when and why polyQ repeat proteins start to aggregate and intoxify cells. We validate emerging hypotheses using in vivo C. elegans and mouse models as well as iPSC-derived neurons and established cell lines. Our research will provide insights into the molecular basis of proteostasis and may identify new routes to ameliorate the pathology of aging-associated neuropathologies.
Beyond paralogs and homologs: Understanding redundancy and diversity amongst Hsp70 chaperones.
Humans encode 17 Hsp70 family genes. We are interested in defining why cells express so many presumably redundant chaperones and whether these chaperones have adopted unique functions that make them essential.