Max Rice

In a collaboration between Franck Polleux and Kapil Ramachandran, I am investigating the function of a newly discovered proteasome complex in the brain called the neuroproteasome. My goal is to characterize the neuroproteasome's function in brain circuits in vivo, as most work on neuroproteasomes has been done in cultured neurons. Previous Institution: McGill University (2018-2022)

In neurons, proteostasis is critical to synaptic plasticity, neuronal development, and intracellular signal transduction. The protein clearance component of proteostasis is largely driven by proteasomal degradation. In 2017, Kapil Ramachandran discovered a unique, neuron-specific type of proteasome, called the neuroproteasome. Unlike cytosolic proteasomes, neuroproteasomes are localized to the plasma membrane, degrading recently translated proteins and releasing small peptide degradation products into the extracellular space. These peptides have been shown to modulate neuronal activity in vitro, but their role in the intact brain is still unclear. To perform loss-of-function studies on neuroproteasomes in the brain, the Ramachandran Lab developed selective neuroproteasome inhibitors, and after using these neuroproteasome inhibitors in mice, the lab observed circuit hyperexcitability and seizures within minutes. This rapid effect suggests that, through unknown mechanisms, neuroproteasome-released peptides suppress circuit hyperexcitability. We believe that the peptides released by neuroproteasomes are responsible for our observations, since any effect due to protein turnover would occur on at least the minutes-hours timescale. Therefore, neuroproteasomes could unveil a novel form of fast, synaptic vesicle-independent neuropeptide modulation in the brain, defining a new mechanism of neuronal proteostasis enabling overall circuit function. Using in vivo genetic labeling and 2-photon calcium imaging, I am trying to determine the synapse types and cell types that are modulated by neuroproteasome peptides. My hope is that I can provide the field with a better understanding of neuroproteasome signaling, which would reveal a new and unusual form of neuromodulation, and it would enable future studies on how neuroproteasomes may influence memory, plasticity, and behavior

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