# Using mouse models to dissect the roles of ZMPSTE24 and prelamin A in accelerated aging

> **NIH NIH R03** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $82,250

## Abstract

PROJECT SUMMARY
Accelerated aging disorders can provide critical insights into aspects of physiological aging. A subset of
accelerated aging disorders, including Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral
dysplasia type B (MAD-B), are characterized by accumulation of farnesylated prelamin A or its variants. Normally,
farnesylated prelamin A is processed to mature lamin A – an intermediate filament protein of the nuclear lamina
– by a proteolytic cleavage near the carboxyl-terminus catalyzed by the zinc metalloproteinase ZMPSTE24.
Defects in this processing resulting from mutations in either LMNA encoding prelamin A or ZMPSTE24
respectively cause HGPS and MAD-B. Some studies have even implicated farnesylated prelamin A or its variants
in physiological aging. However, much remains to be learned about the underlying pathogenic mechanisms of
how prelamin A mediates accelerated and possibly physiological aging. We have generated a mouse with a
point mutation that changes the leucine just downstream from the ZMPSTE24 cleavage site in prelamin A to an
arginine. LmnaL648R/L648R mice express permanently farnesylated prelamin A, with a single amino acid substitution
at residue 648, and no mature lamin A. However, in contrast to Zmpste24-/- mice that have severe progeroid
phenotypes and significantly shortened lifespans, LmnaL648R/L648R mice have more mild and later onset progeroid
features and near-normal longevity. This finding leads to two alterative hypotheses we will test in this R03 small
research project: 1) that ZMPSTE24 has functions related to accelerated aging independent of prelamin A
processing or 2) that a single amino acid substitution in prelamin A renders it less “toxic” than the wild-type
protein with regards to accelerated aging phenotypes. The single Specific Aim is to determine if deletion of
Zmpste24 shortens the lifespan and worsen the progeroid phenotypes of LmnaL648R/L648R mice. To test this
hypothesis, we will cross Lmna+/L648R and Zmpste24+/- mice to generate LmnaL648R/L648R;Zmpste24-/- mice. These
mice will express L648R prelamin A and have no active ZMPSTE24. If they are similar to Zmpste24-/- mice, with
a more severe progeroid phenotype and shorter lifespan than LmnaL648R/L648R mice, it will indicate that ZMPSTE24
has other critical functions in aging. If these “double mutant” mice have a longer lifespan and less severe
progeroid phenotypes than Zmpste24-/- mice, it will indicate that a single amino acid substitution in farnesylated
prelamin A reduces its ability to induce accelerated aging. Data that supports one of these alternative hypotheses
will lead to future projects on either 1) a role of ZMPSTE24 in accelerated aging separate from that of prelamin
A processing or 2) specific functions of the region around leucine 648 in prelamin A in generating accelerated
aging phenotypes.

## Key facts

- **NIH application ID:** 10951313
- **Project number:** 1R03AG088752-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Howard J Worman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $82,250
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951313

## Citation

> US National Institutes of Health, RePORTER application 10951313, Using mouse models to dissect the roles of ZMPSTE24 and prelamin A in accelerated aging (1R03AG088752-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10951313. Licensed CC0.

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