# Munc18-1 mutations disrupt syntaxin-5 stability and general secretory trafficking

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $47,427

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations in Munc18-1 (also called STXBP1) lead to devastating infantile epileptic encephalopathies with
profound intellectual disability, intractable seizures, ataxia, and numerous other symptoms. Munc18-1 controls
neurotransmitter release at the synapse, but recent evidence demonstrates that a non-synaptic Munc18-1-
dependent process, a role in general secretory trafficking, is also perturbed with Munc18-1 loss. Yet, the
causative molecular mechanism for the mistrafficking seen in Munc18-1-/- neurons remains unclear. Preliminary
data reveal that mutations in Munc18-1 cause reduced levels of the Golgi SNARE protein syntaxin-5 (stx5) and
stx5-containing SNARE complexes, as well as an abnormal Golgi morphology. The central hypothesis of this
proposal, based on strong preliminary data, is Munc18-1 mutations cause syntaxin-1 mislocalization and
induce loss of function of stx5, leading to trafficking defects in the Golgi and subsequent non-synaptic
neuronal dysfunction. This impairment in secretory trafficking may partly trigger the developmental dysfunction
seen in Munc18-1 related syndromes. The objective of this proposal to demonstrate how loss of stx5 leads to
neuronal, non-synaptic dysfunction. The rationale for these studies is that revealing the role of stx5 in maintaining
neuronal function will have translational importance in the development of rational treatments for Munc18-1
linked syndromes. Guided by strong preliminary data, this hypothesis will be tested in two specific aims: Aim 1)
Determine how mutant Munc18-1 causes an abnormal Golgi phenotype, and Aim 2) Determine how the stx5
reduction seen in Munc18-1-/- and mutant Munc18-1 neurons affects intracellular protein trafficking and neuron
activity. In the first aim, the nature and cause of this abnormal Golgi morphology will be determined using primary
neurons. First, changes to resident Golgi, ER, and cytoskeletal proteins will be characterized in Munc18-1-/- and
mutant Munc18-1 neurons. Additionally, the effect of stx5 reduction on the Golgi phenotype will be determined,
as well as the effect of syntaxin-1 mislocalization. In the second aim, changes to secretory cargo mistrafficking
due to reduction in stx5 will be determined. Furthermore, the effect of stx5 reduction on neuronal function and
neurite and synapse morphology will be examined. This research is significant, because it will determine the
mechanisms and importance of disturbed secretory trafficking in neurons and the role of stx5 in particular, and
will have translational importance in the development of new treatment strategies. This research is innovative,
because of (1) its novel hypothesis that non-synaptic dysfunction of Munc18-1 contributes to these syndromes,
and (2) its multidisciplinary approach combining biochemical and cell biological approaches to gain insight into
how mutations in Munc18-1 lead to non-synaptic dysfunction.

## Key facts

- **NIH application ID:** 9991345
- **Project number:** 1F30HD100096-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Debra Abramov
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,427
- **Award type:** 1
- **Project period:** 2020-08-03 → 2024-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991345

## Citation

> US National Institutes of Health, RePORTER application 9991345, Munc18-1 mutations disrupt syntaxin-5 stability and general secretory trafficking (1F30HD100096-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991345. Licensed CC0.

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