# Role of UCH-L1 in Ischemic Injury and Recovery

> **NIH NIH RF1** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $2,915,430

## Abstract

Neuroprotective drugs that are highly effective in preventing neuronal cell death in vitro and preventing
gray matter injury in vivo have not been successfully translated into therapies for human stroke. The reasons
hypothesized to explain this failure of translation include the lack of effect of many neuroprotective treatments
on white matter injury and a focus on hyperacute mechanisms that are not practical treatment targets in most
patients with stroke.
 Ubiquitin C-terminal hydrolase L1 (UCHL1) is a multifunctional protein that is selectively expressed in
neurons and axons throughout brain. UCHL1 plays an important role in axonal transport and maintaining
axonal integrity as well as removing abnormal proteins via the ubiquitin proteasome pathway. UCHL1
regulates synaptic function and may be involved in memory function. Humans and mice with mutations in
UCHL1 have extensive motor system abnormalities. We hypothesize that UCLH1 may play an important role in
preserving axonal integrity and synaptic function promoting motor recovery after stroke.
 In the previous cycle of funding, we found that the 152 cysteine of UCHL1 binds reactive lipids and
inactivates the enzyme. We constructed a mouse bearing a mutation that prevents binding at the site (C152A)
and found that this mutation preserves axonal integrity and synaptic function and promotes motor recovery
after cerebral ischemia in vitro and in vivo. We now have constructed a mouse bearing a mutation (C90A) that
abolishes the UCHL1 hydrolase activity. In addition, we have constructed TAT-UCHL1 proteins that readily
transduces neurons after systemic administration.
 We propose the following specific aims:
 Aim 1: Test whether the C90A mutation exacerbates gray and white matter integrity and
exacerbates motor impairment after ischemia
 Aim 2: Test whether treatment with TAT-UCHL1 proteins will reduce gray and white matter injury
and improve axonal conduction, synaptic function and motor behavior after ischemia.
 Aim 3 : Test whether the C152A mutation prevents white matter pathology and cognitive change in
a model of vascular dementia in young and old mice.
 The broad long term objectives of these studies are to develop treatments that promote both gray and
white matter preservation and functional recovery after stroke. These studies will improve scientific knowledge
regarding the role of UCHL1 and in stroke and vascular dementia and test novel TAT-UCHL1 proteins in
preclinical stroke models.

## Key facts

- **NIH application ID:** 9883073
- **Project number:** 2RF1NS037459-18
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** STEVEN H GRAHAM
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,915,430
- **Award type:** 2
- **Project period:** 1999-01-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883073

## Citation

> US National Institutes of Health, RePORTER application 9883073, Role of UCH-L1 in Ischemic Injury and Recovery (2RF1NS037459-18). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/9883073. Licensed CC0.

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