# Sez6 proteins as protection factors in complement-mediated synaptic pruning

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $385,000

## Abstract

Project Summary/Abstract
 Immune dysfunction and imbalances in synaptic pruning have been implicated as contributing factors to
neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Recent studies
suggest that dysregulation of complement may be involved. Complement deposits on neuronal synapses to
mediate synaptic pruning by microglia and refine neural circuits during critical windows of brain development.
Complement can also aberrantly tag synapses for removal in inflammatory and neurodegenerative
diseases. Self-directed complement activity is usually held in check by complement regulatory proteins
expressed on cell membranes. Nevertheless, the role of complement inhibitors has been largely ignored in
studies of complement-mediated synaptic pruning and is the subject of this grant. Our preliminary data shows
that the Sez6 family (consisting of Sez6, Sez6L, and Sez6L2) are novel, complement inhibitors. Sez6 family
members are highly expressed by neurons during development and in adulthood. Sez6 proteins have been
shown to modulate synapse numbers, synaptic plasticity, and dendrite morphology. Genetic loss of Sez6
genes results in impaired cognition and motor deficits. Sez6 family members also have genetic connections to
autism, schizophrenia, intellectual disability, epilepsy, and bipolar disorder. We propose that Sez6 proteins
modulate synapse numbers and brain development by putting the brakes on complement-mediated synaptic
pruning by microglia. Furthermore, disruptions in this process may contribute to the pathogenesis of
neurodevelopmental disorders such as ASD. We will investigate mechanisms of complement regulation by
Sez6 family members and whether these are disrupted by missense mutations previously identifed in ASD
patients. Then will determine if Sez6 family genetic knockout phenotypes are complement-dependent and/or
exacerbated by the inflammatory environment of maternal immune activation. Finally, we will investigate
whether neuronal activity and the endocytic motifs within the cytoplasmic tail of Sez6 proteins differentially
place Sez6 proteins and their complement inhibitory function on the cell surface of active synapses as opposed
to weak and inappropriate synapses. This would couple the functional strength of specific neuronal
connections to synapses that can be tagged and removed by complement-mediated pruning. This research
program will provide insight into the mechanisms of how Sez6 proteins are protective factors against excessive
complement-mediated pruning by microglia that may be especially relevant to the pathogenesis of various
neurodevelopmental disorders such as ASD.

## Key facts

- **NIH application ID:** 10179969
- **Project number:** 1R01NS121130-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** JENNETTA W HAMMOND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179969

## Citation

> US National Institutes of Health, RePORTER application 10179969, Sez6 proteins as protection factors in complement-mediated synaptic pruning (1R01NS121130-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10179969. Licensed CC0.

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