Animals; Disease Models, Animal; Mice; Humans; Spinal Cord/pathology; Amyotrophic Lateral Sclerosis/metabolism; Amyotrophic Lateral Sclerosis/genetics; Amyotrophic Lateral Sclerosis/pathology; Motor Neurons/pathology; Cell Nucleolus/metabolism; Amyotrophic Lateral Sclerosis; Cell Nucleolus; Motor Neurons; Medicine (miscellaneous); Biochemistry, Genetics and Molecular Biology (all)
Abstract :
[en] Dysfunction of Elongator is associated with amyotrophic lateral sclerosis (ALS). Here, we describe mouse models in which either Elongator subunit 1(Elp1) or subunit 3 (Elp3) is selectively ablated in alpha motor neurons of the spinal cord. These mice exhibit a progressive loss of motor strength and motor neuron degeneration. To interrogate the molecular mechanisms that contribute to motor neuron cell death in these mice, we examine multiple disease pathways, including the expression of TDP-43 whose cytoplasmic aggregation is associated with the human disease. Although TDP-43 is a well-characterized nuclear protein functioning in RNA metabolism and gene transcription, here we document TDP-43's robust presence in the nucleolus of wild-type motor neurons and its clearance from both the nucleus and the nucleolus of motor neurons in Elp conditional knockout mice. Thus, this study directly links dysfunction of Elongator with nucleolar disruption and TDP-43 clearing, two hallmark cellular pathologies of ALS.
Disciplines :
Neurology
Author, co-author :
Snow, Magge; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Cameron, BreAnna; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Pond, Renzie; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Trudell, Rachel; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ; College of Veterinary Medicine, Washington State University, Pullman, WA, USA
Snyder, Sara; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Torres-Hernandez, Lauryn ; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Deschamps, Devyn; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ; Department of Neuroscience, Duke University, Durham, NC, USA
Tulimaiau, Danara; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Hawkinson, Kiana; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Russell, Morgan; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Horan, Danielle; Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT, USA
Walters, Joseph; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ; Billings Clinic Department of Psychiatry, Billings Clinic, Billings, MT, USA
Fox, James H; Animal Resources Center, Montana State University, Bozeman, MT, USA
Arlian, Britni; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA
Chariot, Alain ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale ; WELBIO Department, WEL Research Institute, Wavre, Belgium
Nguyen, Laurent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; WELBIO Department, WEL Research Institute, Wavre, Belgium
George, Lynn ; Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA. lynn.george@msubillings.edu
NINDS - National Institute of Neurological Disorders and Stroke NIGMS - National Institute of General Medical Sciences Private donation to the familial dysautonomia and amyotrophic lateral sclerosis research fund in the name of Zak Rosen
Funding text :
This work was supported by the National Institutes of Health, R15NS090384 (L.G.), Award number P20GM103474, and by a private donation to the familial dysautonomia and amyotrophic lateral sclerosis research fund in the name of Zak Rosen (MSU Billings Foundation) (L.G.).
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