# Molecular Interplay of Endocytic Proteins

> **NIH NS R01** · FRED HUTCHINSON CANCER CENTER · 2026 · $638,385

## Abstract

Project summary
Synaptic vesicle endocytosis plays a crucial role in sustaining effective neurotransmission and supporting
neural circuit stability. Disruptions in this process can weaken synaptic signaling, contributing to neurological
disorders such as Parkinson's disease, Down syndrome, and epilepsy. Two proteins that play key roles in
synaptic vesicle recycling are synaptojanin and endophilin. Despite their established roles, the molecular
mechanisms governing their coordinated action at synapses remain poorly understood. Preliminary findings
from our large-scale genetic screen revealed intriguing mutations in synaptojanin that enable it to function
independently of endophilin. This discovery suggests that synaptic deficits in endophilin-null mutants arise from
dysregulation of synaptojanin, as function is nearly fully restored by specific synaptojanin mutations. Our
results point to a novel regulatory mechanism for synaptojanin, focusing on its membrane interactions rather
than solely on protein-protein interactions with endophilin's SH3 domain. In this project, we will investigate the
functional implications of these mutations on synaptojanin's role at the synapse. We hypothesize that mutant
synaptojanin acquires enhanced membrane-remodeling properties, enabling it to support synaptic vesicle
endocytosis without reliance on the membrane-bending protein endophilin. To explore this, we propose to
examine how these mutations impact synaptic physiology in absence of endophilin. We will then investigate
the underlying biochemical mechanisms that coordinate the actions of synaptojanin and endophilin. Finally, we
will evaluate how these mutations affect synaptic function across different life stages, particularly in aging
animals. By uncovering the mechanisms that allow synaptojanin to bypass the need for endophilin, this
research is expected to reshape our understanding of endocytic protein coordination and provide new insights
into synaptic function, with important

## Key facts

- **NIH application ID:** 11362515
- **Project number:** 5R01NS115974-08
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Jihong  Bai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NS
- **Fiscal year:** 2026
- **Award amount:** $638,385
- **Award type:** 5
- **Project period:** 2020-02-15T00:00:00 → 2030-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11362515

## Citation

> US National Institutes of Health, RePORTER application 11362515, Molecular Interplay of Endocytic Proteins (5R01NS115974-08). Retrieved via AI Analytics 2026-07-13 from https://api.ai-analytics.org/grant/nih/11362515. Licensed CC0.

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