Assistant Professor Reut Shalgi
Neurodegenerative diseases (ND) are a class of devastating lethal disorders affecting the brain and nervous system. A common molecular feature to the majority of them, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ALS and others, is the involvement of diverse mutant proteins which lose their proper folding (termed misfolding), and tend to aggregate inside (or in the case of Alzheimer’s, outside) the cells. The master regulators of protein misfolding in the cell are an elaborate network of molecular chaperones, which have evolved in all organisms in order to fold newly synthesized proteins, re-fold proteins that were misfolded due to transient physiological or environmental perturbation (termed proteotoxic stresses), and prevent protein aggregation. Work by numerous labs show that the chaperone network successfully copes with perturbations causing proteotoxic stress, however, in neurodegeneration (ND), the chaperone network fails to protect cells from misfolding and aggregation.
In the Shalgi lab we are interested in the protein homeostasis regulation, from gene expression, through translation, to PQC network structure and function. We are using a systems biology approach to study and integrate information from many regulatory layers, with the overarching goal of revealing underlying principles governing regulation of stress and adaptation, and understand how these go awry during aging and neurodegeneration.
We are studying regulation of stress during cellular aging, i.e. human senescence. This work reveled that proteostasis decline of the proteotoxic stress response is an intrinsic property of human senescent cells, and we are identifying its principles in various regulatory layers.
We are also performing detailed characterization of the functional effects of the PQC network in regulating protein homeostasis. We are exploring the function of each chaperone in the network in coping with stress and with ND-related protein aggregation, asking how we can boost the network’s function specifically to battle NDs. Our ongoing projects on Huntington’s disease and ALS already show promising nodes for intervention.