# CNS Functions of Calpain 5

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $320,887

## Abstract

Abstract:
Calpains are Ca2+-activated, neutral (non-lysosomal) proteases implicated in neurodegeneration
following acute insults such as stroke and traumatic brain injury, as well as in neurodegenerative
disorders such as Alzheimer’s disease. Calpain research in the CNS has focused almost exclusively
on the classical calpains, Calpains 1 and 2. Calpain 5 (CAPN5), which lacks the penta-EF hand
domain of classical calpains, is the 2nd most highly expressed calpain in the CNS. Calpain 5 has
homology to other calpains in the cysteine protease domain and also has a unique C2 domain at the
C-terminus. C2 domains are involved in binding to membranes and lipids. Very little is known
regarding the functions and substrates of Calpain 5. The C. elegans orthologue of Calpain 5, Tra-3,
regulates transcriptional activity involved in sex determination. Tra-3 is also required for
neurodegeneration induced by TDP-43 toxicity and for necrotic death of sensory neurons following
calcium overload. At the subcellular level, CAPN5 is found in nuclear and crude mitochondrial
fractions, and associated with promeylocytic nuclear bodies. The purpose of this proposal is gain
insight into the CNS functions of Calpain 5. Aim 1 will identify Calpain 5 binding partners and
substrates using three complimentary techniques: tandem affinity purification; proximity dependent
localization; and in vitro affinity capture, with each technique paired with mass spectrometry for
protein identification. The binding partners and substrates will be evaluated under both basal and
elevated intracellular calcium conditions. The role of the C2 domain in Ca2+ binding along with
CAPN5 activation and localization will be evaluated in Aim 2. Aim 3 will explore the physiological
functions of CAPN5, utilizing knockout cell lines generated using CRISPR/Cas-9 and conditional
knockout mice. Preliminary data support the feasibility of each Aim. Together, these results will
provide essential information for deciphering the CNS function(s) of CAPN5.

## Key facts

- **NIH application ID:** 9948028
- **Project number:** 5R01NS095229-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** James W. Geddes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $320,887
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948028

## Citation

> US National Institutes of Health, RePORTER application 9948028, CNS Functions of Calpain 5 (5R01NS095229-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948028. Licensed CC0.

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