Protein misfolding diseases, such as Alzheimer's or Parkinson's diseases, ALS, or certain types of diabetes are becoming increasingly prevalent in the aging human population. Protein misfolding is often implicated in these disorders, but the mechanisms remain unclear. We have shown that misfolding and aggregation of disease-related proteins (e.g. polyglutamine expansions in Huntington's disease, or mutant SOD1 in ALS) can trigger misfolding of other metastable 'bystander' proteins, causing their loss of function and thus disrupting cellular functions. On the other hand, these metastable proteins, encoded by genetic polymorphisms, strongly modulate the disease phenotypes. We proposed that competition for the folding resources underlies this toxic behavior. It is currently thought that understanding such failure of protein homeostasis (proteostasis) is key to understanding and combating aging and neurodegeneration. My lab focuses on mechanisms that control proteostasis, using genetic, biochemical, and live imaging approaches in a metazoan C. elegans and mammalian neurons. We currently have three main research directions:
1. The mechanism of differential neuronal susceptibility to protein misfolding. A. Why only some neurons are affected in disease, when the toxic protein is often expressed in all or many neurons? We are using C. elegans to ask whether dysfunction of the susceptible neuron can be explained by misfolding of a 'bystander' protein that is not present in other neurons, and what makes a particular 'bystander' protein a risk factor for a given neuron. B. An exciting new direction that sprung from the above work is the finding that a folding stress in the ER of neurons derails the correct targeting of neurotrophic secreted molecules to axons or dendrites. We are examining the novel function of an ER stress sensor, PERK, in regulating the axonal/dendritic targeting, and whether it explains why mutations in PERK are a risk factor for Alzheimer's disease and tauopathy.
2. The role of natural genetic variation and physiological stress in proteostasis. A. We are using wild strains of C. elegans to understand 1) what is the nature of polymorphisms and genetic networks that control susceptibility of cells to protein aggregation and toxicity, and 2) how natural variation controls resistance to vs. tolerance of aggregation. B. We are harnessing the natural, evolutionarily selected mechanisms that protect proteostasis. For example, we have identified a small heat-shock protein HSP-12.6 as a major defender of proteostasis in the stress-resistant dauer larva, and are testing its mechanism of action.
3. Maintaining the ER proteostasis under physiological stress. A. We are studying how cells match which ER chaperones are induced during differentiation to their future protein folding needs, since different secreted proteins will need different chaperones for their efficient folding. B. In collaboration with Dr. Argon's lab (CHOP) we are studying the regulation of an ER stress sensor IRE1 in adaptation to changes in ER proteostasis, and in collaboration with both Dr. Argon's and Dr. Behtea's labs – the possibility of manipulating the IRE1 activity to improve re-myelination in a Multiple Sclerosis model.