# Molecular determinants of neuronal protein homeostasis through plasma membrane-localized proteasome complexes.

> **NIH NIH DP5** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $401,109

## Abstract

PROJECT SUMMARY / ABSTRACT
 Cells continuously respond to physiological signals and potentially pathological perturbations. In
response, protein synthesis and protein degradation, the latter of which is predominantly driven by the ubiquitin-
proteasome system, reciprocally remodel the intracellular proteome. The dynamics of protein turnover determine
the physiological response to a large diversity of signals or perturbations and have major ramifications on human
physiology. Indeed, over four decades of work on the ubiquitin conjugating cascade and the 26S proteasome
has elucidated essential roles for the ubiquitin-proteasome system in nearly every cellular process. The
prevailing principles in protein turnover have been that ubiquitylation is necessary for substrate tagging and that
the 26S proteasome is the only proteasome species that degrades ubiquitin-protein conjugates. Though 20S
proteasomes form the core of the 26S complex, they remain largely understudied because of a prior lack of clear
evidence for functional 20S particles in cells and no insight into 20S-specific substrate targeting. I recently
discovered a new mechanism of ubiquitin-independent protein turnover through a highly specialized 20S
proteasome that is tightly associated with neuronal plasma membranes. These neuronal membrane
proteasomes (NMPs) directly associate with ribosomes to degrade ~250-500 nascent chain substrates
independent of ubiquitylation. The NMP degrades substrates across the membrane, releasing resulting peptide
fragments into the extracellular space that induce signaling in other neurons, and therefore represents a new
mechanism of neuromodulation. Here, I propose studies that will lay the foundation necessary to understand this
new paradigm in protein turnover. In my first aim, I will identify how NMPs associate with the plasma membrane
and reveal the molecular components of this membrane complex. In the second aim, I will determine how the
specificity of NMP-mediated degradation of nascent chains is achieved. In the final aim, I will gain insights into
the biological processes that NMP-mediated degradation regulates. The proposed research is significant
because it opens a new field of research into non-canonical protein turnover in neurons. This work will generate
the tools and mechanistic insight necessary to understanding how NMP-mediated degradation is codified in and
relevant to the vertebrate nervous system. This will not only shed light onto the new mechanism of
neuromodulation through NMPs, but also provide a framework relevant to abnormalities in protein turnover that
underlie multiple human neuropathologies.

## Key facts

- **NIH application ID:** 10485291
- **Project number:** 5DP5OD028133-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Kapil Ramachandran
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $401,109
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485291

## Citation

> US National Institutes of Health, RePORTER application 10485291, Molecular determinants of neuronal protein homeostasis through plasma membrane-localized proteasome complexes. (5DP5OD028133-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10485291. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*