# Targeted Degradation of Extracellular Proteins to Enhance Brain Plasticity

> **NIH NIH DP1** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2024 · $1,330,000

## Abstract

PROJECT SUMMARY
The young brain displays remarkable plasticity. This includes an ability to remodel neuronal synaptic connections
to learn new tasks in health, as well as being able to repair connections and restore function after injury. In the
adult brain there are active mechanisms in place that maintain neuronal circuit connectivity and synaptic stability,
which is necessary for typical brain function, but acts as a barrier to targeted synaptic remodeling in situations
where this is beneficial, for example to enhance learning, or to repair neurons after injury. Removal of factors
from the adult brain that limit plasticity is sufficient to enable enhanced remodeling and repair. However, these
manipulations lead to a permanent reopening of plasticity states, which is detrimental to long-term brain function
by non-specifically destabilizing synaptic connections. Therefore, new approaches are needed to transiently
enhance neuronal plasticity state to enable controlled synaptic remodeling and repair. There is compelling
evidence that manipulating proteins in the extracellular space surrounding neurons is sufficient to enhance
plasticity and synaptic remodeling. For example, proteins secreted by non-neuronal glial cells, specifically
astrocytes, are sufficient to induce synapse maturation and stabilization, and permanent removal of these factors
from adult astrocytes enables enhanced plasticity and repair. This demonstrates a role for specific secreted
proteins in repressing plasticity in the adult brain, suggesting their targeted removal may be beneficial. Therefore,
the first goal of this proposal is to ask if acute degradation of specific extracellular proteins is able to reopen brief,
controlled, windows of plasticity to enable enhanced learning or to promote synaptic repair after injury. This will
be achieved by developing a genetically encoded system for Targeted Degradation of Extracellular Proteins
(TDEP). TDEP will use nanobodies that bind the protein of interest, coupled to a degradation-targeting sequence
for uptake and removal by endogenous brain cells. As proof-of-concept TDEP will be developed to degrade
known astrocyte-secreted proteins that stabilize synapses, and determine whether acute protein degradation is
sufficient to reopen transient windows of synaptic plasticity, assayed using visual system plasticity, injury models
and learning and memory paradigms. The second goal is to identify the complete repertoire of extracellular
proteins that contribute to repressing plasticity in adulthood, and their cellular source, to enable their precise
targeting for degradation and plasticity enhancement. This will be achieved by labeling newly-synthesized
proteins secreted from specific brain cells under different plasticity conditions, using proximity labeling of proteins
with biotin by the enzyme TurboID, targeted to different subcellular compartments from which extracellular
proteins originate. This will generate an atlas of the cellular ...

## Key facts

- **NIH application ID:** 10916890
- **Project number:** 1DP1NS142487-01
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Nicola J Allen
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,330,000
- **Award type:** 1
- **Project period:** 2024-09-12 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916890

## Citation

> US National Institutes of Health, RePORTER application 10916890, Targeted Degradation of Extracellular Proteins to Enhance Brain Plasticity (1DP1NS142487-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916890. Licensed CC0.

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