Role of TDP-43 in cellular stress responses

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Mammalian cells possess a variety of mechanisms to mediate a cell's recovery from physiological and environmental stresses. Depending on the type of stress encountered, a variety of signaling pathways can be activated resulting in responses ranging from proliferation to growth arrest, senescence, or cell death. At the cellular level, the immediate response to a stress is the formation of cytoplasmic structures called stress granules. Stress granules contain a variety of large protein complexes which cooperatively maintain mRNAs in a silent state. One protein we have recently identified as being a component of stress granules is TAR DNA binding protein (TDP-43). TDP-43 is a member of a large family of RNA binding proteins known as heterogeneous nuclear ribonucleoproteins (hnRNPs), some of which have been reported to participate in cellular stress responses. The proposed research program aims to define the role of TDP-43 in cellular stress responses. The proposal incorporates a variety of cell biology, biochemistry and mass spectrometry approaches. Graduate students participating in this program will gain a diversified training in these methods as well as data analysis. Understanding stress granule signaling and dynamics via TDP-43 will have wide-reaching implications for cellular responses to physiological and environmental stimuli.