# Role of UCHL1 in Axonal Injury and Recovery after TBI

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $404,662

## Abstract

Diffuse axonal injury is a major component of the motor and cognitive sequela of
traumatic brain injury (TBI). Ubiquitin C-terminal hydrolase L1 (UCHL1) is expressed at high
concentrations in neurons and may play an important role axonal transport and synaptic
function. UCHL1's activity is important in degrading abnormal neuronal protein via the ubiquitin
proteasome pathway. Thus, UCHL1 may play an important role in recovery after injury via
several mechanisms. In preliminary studies, a TAT-UCHL1 protein was constructed that readily
enters the brain when given i.p. Treatment with TAT-UCHL1 reduced axonal injury detected by
APP immunocytochemistry and decreased hippocampal cell death after controlled cortical
impact (CCI) in mice. A reactive lipid binding site at the 152 cysteine of UCHL1 was identified
that is responsible for unfolding and inactivating the enzyme. A knock-in mouse bearing a
C152A mutation was constructed and found to have significantly reduced axonal injury and
improved motor behavior after CCI. A mouse bearing a C90A mutation with UCHL1 activity that
is devoid of hydrolase activity was also constructed.
 The goals of the current study are: 1) Determine the role of the UCHL1 C152 site in
axonal injury, neuronal death, and motor and cognitive behavior after CCI in mice. 2)
Determine the role of UCHL1 hydrolase activity in axonal injury, neuronal death, and
motor and cognitive behavior after CCI in mice. 3) Test whether systemic treatment with
TAT-UCHL1 fusion proteins will reduce axonal injury in the in vitro stretch model and in
vivo TBI model, and improve long term motor and cognitive function after CCI in mice.
 The broad long term objective of these studies is to develop novel approaches that
promote axonal preservation and functional recovery after TBI. Completion of these studies will
improve scientific knowledge regarding the role of UCHL1 in neuronal repair and functional
recovery after TBI and test novel TAT-UCHL1 proteins as a novel strategy to address axonal
injury.

## Key facts

- **NIH application ID:** 9970552
- **Project number:** 5R01NS102195-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** C EDWARD DIXON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $404,662
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970552

## Citation

> US National Institutes of Health, RePORTER application 9970552, Role of UCHL1 in Axonal Injury and Recovery after TBI (5R01NS102195-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9970552. Licensed CC0.

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