# SNARE complex-mediated exocytosis in oligodendrocyte differentiation and survival

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT STORRS · 2024 · $338,475

## Abstract

Multiple sclerosis is a chronic demyelinating disease affecting primarily people during their
active years of life. Long-lasting demyelination leads to axonal degeneration with severe
neurological deficits, and in most cases remyelination is limited. Remyelination failure could
occur due to the inability of existing oligodendrocytes (OLs) to myelinate demyelinated axons or
failure of oligodendrocyte precursor cells (OPCs) to generate myelinating OLs in the lesion.
 The dynamics of OLs lineage cells is intricately modulated by the local neural activity. OPCs
receive synaptic and non-synaptic signals from neurons and undergo depolarization or increase
intracellular Ca2+. However, exactly how OPCs sense the level of neuronal activity and initiate a
signaling cascade that triggers a terminal differentiation and survival response has remained
unclear. In neurons, depolarization-induced Ca2+ entry into axons triggers release of
neurotransmitters from synaptic vesicles clustered at the presynaptic terminal by a series of
molecular events that involve SNARE (soluble N-ethylmaleimide-sensitive factor attachment
protein receptor) proteins. OL lineage cells also express various SNARE proteins and transcripts. Our preliminary results of inactivating vesicular SNARE proteins in OPCs and their progeny revealed that SNARE-
dependent mechanisms are critical for the proper generation of viable OLs. These observations led
us to hypothesize that vesicular SNARE-dependent exocytosis in late OPCs is triggered by
neuronal signals and has a critical autocrine function to promote OL differentiation and survival
of new OLs. This will be tested by 1) fate analysis of divided OPCs that have defective vesicular
SNAREs to determine whether loss of Vesicle-associated membrane protein 2 and/or 3
(VAMP2/3) function compromises OL differentiation and survival (Aim 1); 2) imaging SNARE-
containing vesicles and exocytosis events in cultured OPCs and in vivo to determine whether
neuronally derived signals promote SNARE-mediated exocytosis and clustering of vesicles
(Aim 2); and 3) a proteomics approach to identify the autocrine signal(s) that is released from
OPCs in a SNARE-dependent manner (Aim 3).  The project will establish experimental evidence for a novel principle regarding the cellular mechanism by which late OPCs trigger their terminal differentiation and survival programs in
response to neuronal signals.

## Key facts

- **NIH application ID:** 10813083
- **Project number:** 5R01NS116182-05
- **Recipient organization:** UNIVERSITY OF CONNECTICUT STORRS
- **Principal Investigator:** Akiko Nishiyama
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $338,475
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813083

## Citation

> US National Institutes of Health, RePORTER application 10813083, SNARE complex-mediated exocytosis in oligodendrocyte differentiation and survival (5R01NS116182-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10813083. Licensed CC0.

---

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