Research

Overview

Neurodegenerative diseases (NDs) pose a major societal and economic burden and impart a devastating impact on patients and their family caretakers. A unifying theme that connects these NDs is their strong association with an aging-dependent, 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 chaperone proteins in neurodegeneration and aging, 3) regulation of protein aggregation processes, and 4) 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.

As we age, the functionality of our proteostasis machinery declines, making it more difficult for cells to defend against protein misfolding and cellular stress. This increases the likelihood of aberrant protein aggregation, an inherent component of neurodegenerative disease pathologies.

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" (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.

Cartoon depicting FIC-1/HYPE-mediated AMPylation of BiP.

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.

For both projects, emerging hypotheses will be validated using human tissue culture (TC) models as well as ex vivo human brain tissue from healthy donors, and ND patients. Our research will provide insights into the molecular basis of proteostasis and may identify new routes to ameliorate the pathology of aging-associated neuropathologies.