title: X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron.
abstract: ATP7A is a copper-transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia and failure to thrive, due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked spinal muscular atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice, resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions and a loss of motor neuron cell bodies. Taken together, these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts the spinal motor neuron.
authors: Department of Biochemistry, University of Missouri, Columbia, MO, USA.|Christopher S Bond Life Science Center, University of Missouri, Columbia, MO, USA.
authors: Victoria L
authors: VL
authors: Hodgkinson
authors: Department of Biological Sciences, University of Missouri, Columbia, MO, USA.|Christopher S Bond Life Science Center, University of Missouri, Columbia, MO, USA.
authors: Jeffery M
authors: JM
authors: Dale
authors: Department of Biological Sciences, University of Missouri, Columbia, MO, USA.|Christopher S Bond Life Science Center, University of Missouri, Columbia, MO, USA.
authors: Michael L
authors: ML
authors: Garcia
authors: Department of Biochemistry, University of Missouri, Columbia, MO, USA.|Christopher S Bond Life Science Center, University of Missouri, Columbia, MO, USA.
authors: Gary A
authors: GA
authors: Weisman
authors: Redox Biology Center, University of Nebraska, Lincoln, NE, USA.
authors: Jaekwon
authors: J
authors: Lee
authors: Marine Biological Laboratory, Woods Hole, MA, USA.
authors: Jonathan D
authors: JD
authors: Gitlin
authors: Department of Biochemistry, University of Missouri, Columbia, MO, USA.|Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA.|Christopher S Bond Life Science Center, University of Missouri, Columbia, MO, USA.
authors: Michael J
authors: MJ
authors: Petris
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D027682:Cation Transport Proteins / Q000172:deficiency* / Q000235:genetics; D003300:Copper / Q000378:metabolism; D000073840:Copper-Transporting ATPases; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007794:Lameness, Animal / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D018482:Muscle, Skeletal / Q000294:innervation; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense / Q000235:genetics; D013116:Spinal Cord / Q000737:chemistry
chemical_list: C486201:Atp7a protein, mouse; D027682:Cation Transport Proteins; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases
keywords: ATP7A; Menkes disease; X-linked spinal muscular atrophy; copper; motor neuron; motor neuropathy
references: PLoS One. 2012;7(8):e43039
references: 22900086
references: Am J Physiol Gastrointest Liver Physiol. 2012 Dec 1;303(11):G1236-44
references: 23064757
references: J Neurosci. 2005 Jan 5;25(1):239-46
references: 15634787
references: Neuron. 1999 Aug;23(4):659-74
references: 10482234
references: Nat Chem Biol. 2014 Dec;10(12):1034-42
references: 25344811
references: Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5245-9
references: 15781854
references: Nature. 2006 Feb 23;439(7079):988-92
references: 16372019
references: Mol Neurobiol. 2006 Apr;33(2):81-90
references: 16603790
references: N Engl J Med. 2008 Feb 7;358(6):605-14
references: 18256395
references: Am J Hum Genet. 2010 Mar 12;86(3):343-52
references: 20170900
references: Nat Rev Neurol. 2011 Jan;7(1):15-29
references: 21221114
references: Nature. 2012 Jul 26;487(7408):443-8
references: 22801498
references: Neuron. 2001 May;30(2):399-410
references: 11395002
references: J Nutr. 1983 Oct;113(10):2048-58
references: 6312000
references: J Nutr. 1991 Mar;121(3):355-63
references: 1848285
references: EMBO J. 1996 Nov 15;15(22):6084-95
references: 8947031
references: J Neurosci Methods. 1997 Oct 3;76(2):183-91
references: 9350970
references: Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):5980-5
references: 21444780
references: Cell. 2011 Jul 8;146(1):178-178.e1
references: 21729788
references: Hum Mol Genet. 2012 Apr 15;21(8):1794-807
references: 22210628