# An in vivo approach to understanding mutant PFN1 toxicity on motor neurons

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $366,406

## Abstract

PROJECT SUMMARY
ALS, also known as Lou Gehrig’s disease, is an incurable neurodegenerative disease caused by the
loss of motor neurons leading to paralysis and eventually death. To understand the disease
mechanism and develop therapeutics, mammalian models that phenocopy human disease are
indispensable. For more than two decades, transgenic animals expressing mutant SOD1 gene were
the only model available that faithfully represented the human disease and played an essential role
in advancing our understandings of ALS and enabling therapeutic development. However, due to
the lack of animal models from other ALS-causal genes, it has been difficult to verify and generalize
the mechanistic and therapeutic findings from the mutant SOD1 models. Consequently, we do not
know whether the mechanistic findings from the SOD1 models are common to different mutant
genes or it is specific for SOD1 mutations alone. This has hampered our understanding of ALS and
therapeutic development. Thus, construction of additional mammalian models that mimic ALS
disease process in human is crucial in our fight against ALS. However, efforts in developing new
mammalian models with progressive ALS phenotypes leading to motor neuron loss, clinical
paralysis and death has proven difficult. To solve this problem, we have constructed a transgenic
mouse model by expressing mutant profilin1 gene (PFN1C71G), a recently discovered ALS gene. We
show that expression of the mutant, but not the wild type (PFN1WT) gene, caused a late onset motor
dysfunction phenotype that subsequently progressed to paralysis and death. Furthermore, the
mutant mice developed a relentless progression of motor neuron degeneration and lose a majority
of their motor neurons at the end stage. These results demonstrate that mutant PFN1 causes ALS
by a gain of toxicity and establish a progressive ALS disease model that closely phenocopy the
human disease. These mice provide a new in vivo system for study of disease mechanisms and
therapeutics for ALS. This proposal take advantage of this new model and seeks mechanistic
insights on motor neuron degeneration. Aim 1 will differentiate between two mechanisms of mutant
PFN1 toxicity, a gain of novel toxic property by the mutant protein vs. a dominant-negative inhibition
of the normal PFN1 allele. Aim 2 will explore the underlying cellular determinants for the disease
onset and the rate of disease progression. Aim 3 will investigate the role of ER damage in mutant
PFN1-induced motor neuron degeneration. We will compare the findings from these aims with the
findings from mutant SOD1 models to determine common or gene-specific mechanisms. By these
understanding, better therapeutic approaches may be achieved.

## Key facts

- **NIH application ID:** 9893934
- **Project number:** 5R01NS101895-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** ZUOSHANG XU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $366,406
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893934

## Citation

> US National Institutes of Health, RePORTER application 9893934, An in vivo approach to understanding mutant PFN1 toxicity on motor neurons (5R01NS101895-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9893934. Licensed CC0.

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