# Molecular mechanisms underlying neuronal integrity

> **NIH NIH F31** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $39,956

## Abstract

ABSTRACT
Neurons have an astonishing ability to maintain their integrity throughout an organism’s lifespan. Both the
functional and structural integrity are required for neurons to carry out their biological and behavioral tasks.
Disruption of neuronal integrity compromises brain function and can lead to a myriad of neurological and
psychiatric disorders. To date, the molecular underpinnings for neurons to maintain integrity is unknown, largely
due to the enormous complexity of the human brain. In this proposal, I aim to develop a strategy using the simple
nervous system of the nematode C. elegans to identify molecular mechanisms required for neuronal integrity.
My working hypothesis is that the endocytic protein FCHO-1 is essential for neurons to maintain both functional
and structural integrity. Our preliminary data from electrophysiological analyses demonstrated a significant
decrease of synaptic transmission in fcho-1 mutants. Consistent with compromised neuron activities, the fcho-1
mutant worms exhibit defects in the locomotion behavior. Importantly, my electronic microscopy experiments
uncovered a fascinating and unexpected phenotype; neighboring neurons are abnormally connected to
neighbors in the absence of FCHO-1. To understand how FCHO-1 protects neuronal integrity, I have designed
experiments with two Specific Aims. Aim 1 will determine the role of FCHO-1 in protecting neurons from
abnormally sharing their contents with neighbors. Decades of research have established that each type of
neurons carries specialized contents such as proteins and signaling molecules, which allow neurons to perform
distinct functions. My working hypothesis is that, in the absence of fcho-1, neurons lose structural integrity and
fail to preserve their specialized contents. I predict that neurons will share their protein contents with neighbor
cells due to damages of cellular boundaries. To monitor the impact of FCHO-1 on structural integrity (i.e.,
preventing neurons from abnormally exchange cellular contents with neighbor cells), I have developed a novel
PAGEN assay (protease-assisted gene activation) to follow abnormal exchange of proteins between neurons.
Aim 2 will elucidate the molecular mechanism by which FCHO-1 protects the structural integrity of neurons. My
working hypothesis is that FCHO-1 is required for the recycling of adherens junction proteins at neuron-neuron
boundaries. In support of this idea, I observed that, in fcho-1 mutants, the abnormal connections between
neurons occur at protein dense regions reminiscent of adherens junctions. I expect that disruption of the
endocytic protein FCHO-1 will impair the internalization of adherens junction proteins, which subsequently
destabilizes cellular boundaries between neurons and their neighbors. I will examine the role of FCHO-1
dependent endocytic pathways using genetic analyses. Together, results generated from this study will uncover
novel mechanisms for FCHO-1 to support neuron integrity. Eluc...

## Key facts

- **NIH application ID:** 10067095
- **Project number:** 1F31NS118844-01
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Monet A. Jimenez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $39,956
- **Award type:** 1
- **Project period:** 2021-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067095

## Citation

> US National Institutes of Health, RePORTER application 10067095, Molecular mechanisms underlying neuronal integrity (1F31NS118844-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067095. Licensed CC0.

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