# Characterization of a mouse model of KIF5A-associated ALS

> **NIH NIH R03** · OHIO STATE UNIVERSITY · 2020 · $156,000

## Abstract

ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of
upper and lower motor neurons (MN), leading to weakness and eventually death by respiratory failure. There is
no effective treatment, however recent advances in the genetics of ALS, and to the success of gene therapy in the
motor neuron disease spinal muscular atrophy has resulted in increasing optimism that, for certain genetic forms of
ALS, there may so be hope for meaningful disease modifying therapies. Whole genome/exome sequencing and
genome-wide association studies (GWAS) recently revealed that ALS-associated single nucleotide variants are
located in the C-terminal domain of the kinesin KIF5A. KIF5A is a neuron-specific cytoskeletal motor protein
responsible for the anterograde axonal transport of diverse proteins, ribonucleoproteins and cellular organelle
cargos such as mitochondria. The protein is composed of three functional domains; 1) an N-terminal/coiled-
coiled motor domain responsible for microtubule binding and movement, 2) a central “stalk” domain, and 3) a
C-terminal/cargo binding domain. Remarkably, missense mutations in the N-terminal region had been
previously reported in people with hereditary spastic paraparesis (HSP), many with features of hereditary
axonal motor neuropathy (CMT2). These N-terminal mutations appear to result in a loss of the kinesin function
that would be predicted to affect all cargos of KIF5A. In this project, we will to characterize a new ALS mouse
model linked to a mutation in the cargo-binding domain of KIF5A gene. We have created a novel mouse model
of ALS by introducing a splice site variant (c.3005+1G>A) in the mouse Kif5a gene that is the homolog to the
recently reported human c.3020+1G>A KIF5A mutation associated with ALS using CRISPR/Cas9. Here, we
propose a comprehensive behavioral, electrophysiological and pathological characterization of this mouse
model as a first step to understand the functional consequences of KIF5A ALS-associated mutations and to
create a tool for future preclinical and basic science studies.

## Key facts

- **NIH application ID:** 9958497
- **Project number:** 1R03NS116303-01
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Stephen J. Kolb
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 1
- **Project period:** 2020-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9958497

## Citation

> US National Institutes of Health, RePORTER application 9958497, Characterization of a mouse model of KIF5A-associated ALS (1R03NS116303-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9958497. Licensed CC0.

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