title: Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease.
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.
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fil
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Abigail
authors.initials: A
authors.lastname: DeLoach
authors.affiliation: Physiology and Biophysics.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Duah
authors.initials: D
authors.lastname: Alkam
authors.affiliation: Department of Neurobiology and Developmental Sciences.
authors.forename: Melanie
authors.initials: M
authors.lastname: MacNicol
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: Awantika
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutical Sciences.
authors.forename: Cesar M
authors.initials: CM
authors.lastname: Compadre
authors.affiliation: Division of Endocrinology, University of Arkansas for Medical Sciences, AR, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Goellner
authors.affiliation: Division of Endocrinology, University of Arkansas for Medical Sciences, AR, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.affiliation: Department of Pharmacology and Toxicology.
authors.forename: Tariq
authors.initials: T
authors.lastname: Fahmi
authors.affiliation: Department of Pharmacology and Toxicology.|Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors.forename: Alexei G
authors.initials: AG
authors.lastname: Basnakian
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.affiliation: Department of Neurology, Northwestern University, Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL 6011, USA.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Klessner
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
authors.forename: Flint M
authors.initials: FM
authors.lastname: Beal
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Peters
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Metterville
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA.
authors.forename: Karen K Y
authors.initials: KKY
authors.lastname: Ling
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, 10065, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Department of Neurology, Northwestern University, Feinberg School of Medicine, 303 E. Chicago Ave, Chicago, IL 6011, USA.
authors.forename: P Hande
authors.initials: PH
authors.lastname: Ozdinler
authors.affiliation: Department of Pharmacology and Toxicology.|Physiology and Biophysics.|Center for Translational Neuroscience.|Department of Neurology.|Department of Geriatrics, The University of Arkansas for Medical Sciences, AR, USA.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D051304:Profilins / Q000096:biosynthesis* / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
chemical_list: D051304:Profilins