Neurons are postmitotic cells that synthesize many fold more protein than mitotic cells, have an exquisitely dynamic proteome subject to changes in neuronal activity and subcellular localization, yet live for decades without accumulating protein aggregates. There is an almost implicit requirement for unique neuronal mechanisms for maintaining proteostasis. We discovered a new mechanism of protein degradation, which we term the “neuroproteasome”. In essence, we made a fascinating observation that proteasomes in excitatory neurons are localized to the neuronal plasma membrane, degrading substrates co-translationally during states of elevated neuronal activity. This is not only as a new system of protein degradation, but this degradation generates a large set of 4-18aa extracellular peptides which can act as neuromodulators and directly influence the activity of other cells in the brain. Our findings controvert dogma in three ways

1. Proteasomes have historically considered to be intracellular complexes. The neuroproteasome is the first description of a plasma-membrane-bound and functionally transmembrane complex.

2. Ubiquitin and ubiquitin ligases have historically been the primary mechanisms to specify which substrates get turned over. Neuroproteasome-mediated degradation is ubiquitin-independent, which begs the question how substrates are selected for co-translational degradation.

3. The resulting products of degradation have historically thought to be immediately broken down into constituent amino acids. Neuroproteasome-derived peptides are released into the extracellular space, where they act as a new mechanism of signaling through yet-to-be-identified receptors, establishing new receptor-ligand relationships in the brain.

My laboratory seeks to establish a new field in molecular neuroscience by revealing the mechanisms underlying neuroproteasome-mediated protein degradation and the functions of the new mechanism of signaling through neuroproteasome-mediated peptides. We leverage approaches from any discipline to address how neuroproteasomes are regulated and how they modify neuronal structure and function, including super-resolution live microscopy, quantitative proteomics, fast calcium imaging, biochemistry, and chemical biology. We also have a keen eye towards understanding how neuroproteasomes are dysregulated in neurodegenerative disease and over the course of normal physiological aging. Our research program will define neuroproteasomes as a bona fide hub of proteostasis and neuroproteasome-mediated peptide signaling as a new mechanism of neuromodulation. In the long run, we seek to leverage this framework to understand how neuroproteasome localization is modified over aging and neurodegenerative conditions and how to manipulate neuroproteasome localization and function for benefit.