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Hum Mol Genet. 2017 Feb 15;26(4):686-701. doi: 10.1093/hmg/ddw429.

Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease.

Author information

1
Department of Pharmacology and Toxicology.
2
Physiology and Biophysics.
3
Department of Neurobiology and Developmental Sciences.
4
Department of Pharmaceutical Sciences.
5
Division of Endocrinology, University of Arkansas for Medical Sciences, AR, USA.
6
Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
7
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
8
Department of Neurology, Northwestern University, Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL 6011, USA.
9
Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
10
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA.
11
Center for Translational Neuroscience.
12
Department of Neurology.
13
Department of Geriatrics, The University of Arkansas for Medical Sciences, AR, USA.

Abstract

The recent identification of profilin1 mutations in 25 familial ALS cases has linked altered function of this cytoskeleton-regulating protein to the pathogenesis of motor neuron disease. To investigate the pathological role of mutant profilin1 in motor neuron disease, we generated transgenic lines of mice expressing human profilin1 with a mutation at position 118 (hPFN1G118V). One of the mouse lines expressing high levels of mutant human PFN1 protein in the brain and spinal cord exhibited many key clinical and pathological features consistent with human ALS disease. These include loss of lower (ventral horn) and upper motor neurons (corticospinal motor neurons in layer V), mutant profilin1 aggregation, abnormally ubiquitinated proteins, reduced choline acetyltransferase (ChAT) enzyme expression, fragmented mitochondria, glial cell activation, muscle atrophy, weight loss, and reduced survival. Our investigations of actin dynamics and axonal integrity suggest that mutant PFN1 protein is associated with an abnormally low filamentous/globular (F/G)-actin ratio that may be the underlying cause of severe damage to ventral root axons resulting in a Wallerian-like degeneration. These observations indicate that our novel profilin1 mutant mouse line may provide a new ALS model with the opportunity to gain unique perspectives into mechanisms of neurodegeneration that contribute to ALS pathogenesis.

PMID:
28040732
PMCID:
PMC5968635
DOI:
10.1093/hmg/ddw429
[Indexed for MEDLINE]
Free PMC Article

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