Fulya Turker

Background

About Fulya Turker

My research over the past seven years has focused on uncovering the novel signaling role of the proteasome, the main non-lysosomal protein degradation machinery, in the mammalian nervous system, both under normal conditions and during neurodegenerative diseases. The proteasome, essential for all eukaryotic cells, produces short peptide molecules as a result of the breakdown of proteins. Interestingly, in addition to their major role in maintaining protein homeostasis, proteasomes have unique roles in neurons and are critical contributors to neuronal function and survival, with recently described roles in the modulation of neuronal signaling. In 2017, Margolis lab discovered that proteasomes localize to the plasma membrane specifically in neuronal cells, termed the neuronal membrane proteasome (NMP). The localization of the proteasome to the plasma membrane is drastically reduced in an Alzheimer’s disease (AD) model, promoting Tau aggregate accumulation, which suggests a potential role for the NMP in initiation and progression of neurodegenerative diseases. More interestingly, we showed that, upon neuronal stimulation, the NMP degrades newly synthesized intracellular proteins into extracellular peptides, pointing to a novel co-translational degradation mechanism. We developed protocols for the use of activity-based probes (ABPs) measuring proteasome catalytic activity and we showed NMP being catalytically more active once the neuron is stimulated. Finally, we showed that these NMP-derived peptides, once applied to naïve neurons, induce neuronal stimulation as shown by calcium influx and upregulation of gene expression and protein levels of activity-regulated genes. Thus, we hypothesize that NMP peptides drive a novel form of neuronal communication, responsible for modulating neuronal signaling in health and disease. In my lab, we focus on (1) studying the regulation of NMP proteolytic activity and NMP peptide production by using ABPs,(2) defining the differential role(s) of pre- and post-synaptic neurons in NMP peptide-induced neuronal signaling by generating a NMP peptides-on-a-chip microfluidics platform, and (3) characterization and amino acid sequence identification of bioactive NMP peptides via unbiased peptidomics approach in healthy and Alzheimer’s disease state.