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

TitleMutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease.
Publication TypeJournal Article
Year of Publication2017
AuthorsFil D, DeLoach A, Yadav S, Alkam D, MacNicol M, Singh A, Compadre CM, Goellner JJ, O'Brien CA, Fahmi T, Basnakian AG, Calingasan NY, Klessner JL, Beal FM, Peters OM, Metterville J, Brown RH, K Y Ling K, Rigo F, P Ozdinler H, Kiaei M
JournalHum Mol Genet
Volume26
Issue4
Pagination686-701
Date Published2017 02 15
ISSN1460-2083
KeywordsAmino Acid Substitution, Amyotrophic Lateral Sclerosis, Animals, Brain, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Mutation, Missense, Profilins, Spinal Cord
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.

DOI10.1093/hmg/ddw429
Alternate JournalHum. Mol. Genet.
PubMed ID28040732
Grant ListI01 BX002425 / BX / BLRD VA / United States
R01 NS085161 / NS / NINDS NIH HHS / United States
P30 GM110702 / GM / NIGMS NIH HHS / United States
P20 GM109005 / GM / NIGMS NIH HHS / United States
R21 NS088653 / NS / NINDS NIH HHS / United States
R01 HD087057 / HD / NICHD NIH HHS / United States
R21 NS085750 / NS / NINDS NIH HHS / United States
R01 NS088689 / NS / NINDS NIH HHS / United States
R01 FD004127 / FD / FDA HHS / United States
R01 NS079836 / NS / NINDS NIH HHS / United States
R01 NS065847 / NS / NINDS NIH HHS / United States
R01 NS073873 / NS / NINDS NIH HHS / United States