Paraplegin Explained

Paraplegin is a protein that in humans is encoded by the SPG7 gene located on chromosome 16.^{[1] [2] [3]}

Structure

The SPG7 gene contains 21 exons and encodes for a protein that is approximately 88 kDa in size. Two transcript variants encoding distinct isoforms have been identified for this gene.

The structure of the SPG7 resolved by X-ray crystallography reveals that the protein functions as a hexamer and is structurally most similar to bacterial FtSH proteases. It contains an FtsH-homology protease domain as well as an AAA+ homology ATPase domain. The protein is thought to use ATPase-driven conformational changes to the AAA-domain in order to deliver the substrate peptides to be degraded to its protease core.^[4]

Function

The SPG7 protein is a nuclear-encoded metalloprotease protein that is a member of the AAA protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The SPG7 protein is a transmembrane protein that is located to the inner mitochondrial membrane, and is part of the m-AAA metalloproteinase complex, which constitutes one of the known intra-mitochondrial proteases that function in mitochondrial protein quality control.

Interactions

SPG7 interacts with AFG like AAA ATPase 2 (AFG3L2) on the mitochondrial inner membrane to form the m-AAA metalloproteinase complex.

Clinical significance

Mutations associated with this gene cause autosomal recessive spastic paraplegia 7, a neurodegenerative disorder that is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. SPG7 mutations have also been associated with other undiagnosed ataxia.^{[5] [6] [7]}

In model animals, knockdown of spastic paraplegia 7 by siRNA inhibits the early stages of HIV-1 replication in 293T cells infected with VSV-G pseudotyped HIV-1.^[8] It has been shown that an SPG7 variant escapes phosphorylation-regulated processing by AFG3L2 and increases mitochondrial reactive oxygen species generation and is correlated with many clinical phenotypes.^[9] Furthermore, SPG7 deficiency is associated with abnormal mitochondrial DNA maintenance, which may lead to secondary mitochondrial DNA lesions and impaired respiratory activities and mitochondrial functions.^[10]

Further reading

• Pullman WE, Bodmer WF . Cloning and characterization of a gene that regulates cell adhesion . Nature . 356 . 6369 . 529–32 . Apr 1992 . 1560826 . 10.1038/356529a0 . 1992Natur.356..529P . 9946996 .
• Koyama K, Emi M, Nakamura Y . The cell adhesion regulator (CAR) gene, TaqI and insertion/deletion polymorphisms, and regional assignment to the peritelomeric region of 16q by linkage analysis . Genomics . 16 . 1 . 264–5 . Apr 1993 . 8098008 . 10.1006/geno.1993.1173 .
• Pullman WE, Bodmer WF . Cloning and characterization of a gene that regulates cell adhesion . Nature . 361 . 6412 . 564 . Feb 1993 . 8429914 . 10.1038/361564c0 . free .
• Durbin H, Novelli MR, Bodmer WF . Genomic and cDNA sequence analysis of the cell matrix adhesion regulator gene . Proceedings of the National Academy of Sciences of the United States of America . 94 . 26 . 14578–83 . Dec 1997 . 9405655 . 25060 . 10.1073/pnas.94.26.14578 . 1997PNAS...9414578D . free .
• Settasatian C, Whitmore SA, Crawford J, Bilton RL, Cleton-Jansen AM, Sutherland GR, Callen DF . Grant Robert Sutherland . Genomic structure and expression analysis of the spastic paraplegia gene, SPG7 . Human Genetics . 105 . 1–2 . 139–44 . 1999 . 10480368 . 10.1007/s004399900087 .
• Kremmidiotis G, Gardner AE, Settasatian C, Savoia A, Sutherland GR, Callen DF . Grant Robert Sutherland . Molecular and functional analyses of the human and mouse genes encoding AFG3L1, a mitochondrial metalloprotease homologous to the human spastic paraplegia protein . Genomics . 76 . 1–3 . 58–65 . Aug 2001 . 11549317 . 10.1006/geno.2001.6560 .
• McDermott CJ, Roberts D, Tomkins J, Bushby KM, Shaw PJ . Spastin and paraplegin gene analysis in selected cases of motor neurone disease (MND) . Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders . 4 . 2 . 96–9 . Jun 2003 . 14506940 . 10.1080/14660820310012718 . 45890908 .
• Pirozzi M, Quattrini A, Andolfi G, Dina G, Malaguti MC, Auricchio A, Rugarli EI . Intramuscular viral delivery of paraplegin rescues peripheral axonopathy in a model of hereditary spastic paraplegia . The Journal of Clinical Investigation . 116 . 1 . 202–8 . Jan 2006 . 16357941 . 1312020 . 10.1172/JCI26210 .
• Elleuch N, Depienne C, Benomar A, Hernandez AM, Ferrer X, Fontaine B, Grid D, Tallaksen CM, Zemmouri R, Stevanin G, Durr A, Brice A . Mutation analysis of the paraplegin gene (SPG7) in patients with hereditary spastic paraplegia . Neurology . 66 . 5 . 654–9 . Mar 2006 . 16534102 . 10.1212/01.wnl.0000201185.91110.15. 23463503 .
• Warnecke T, Duning T, Schwan A, Lohmann H, Epplen JT, Young P . A novel form of autosomal recessive hereditary spastic paraplegia caused by a new SPG7 mutation . Neurology . 69 . 4 . 368–75 . Jul 2007 . 17646629 . 10.1212/01.wnl.0000266667.91074.fe . 20106633 .

External links

• GeneReviews/NCBI/NIH/UW entry on Spastic Paraplegia 7

Notes and References

1. Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A . Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease . Cell . 93 . 6 . 973–83 . Jun 1998 . 9635427 . 10.1016/S0092-8674(00)81203-9 . free .
2. De Michele G, De Fusco M, Cavalcanti F, Filla A, Marconi R, Volpe G, Monticelli A, Ballabio A, Casari G, Cocozza S . A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3 . American Journal of Human Genetics . 63 . 1 . 135–9 . Jul 1998 . 9634528 . 1377251 . 10.1086/301930 .
3. Web site: Entrez Gene: SPG7 spastic paraplegia 7, paraplegin (pure and complicated autosomal recessive).
4. Karlberg T, van den Berg S, Hammarström M, Sagemark J, Johansson I, Holmberg-Schiavone L, Schüler H . Crystal structure of the ATPase domain of the human AAA+ protein paraplegin/SPG7 . PLOS ONE . 4 . 10 . e6975 . 2009 . 19841671 . 2734466 . 10.1371/journal.pone.0006975 . 2009PLoSO...4.6975K . free .
5. Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, Fawcett K, Sims D, Eglon G, Hadjivassiliou M, Horvath R, Németh A, Chinnery PF . SPG7 mutations are a common cause of undiagnosed ataxia . Neurology . 84 . 11 . 1174–6 . 2015 . 25681447 . 4371411 . 10.1212/WNL.0000000000001369 .
6. Warnecke T, Duning T, Schirmacher A, Mohammadi S, Schwindt W, Lohmann H, Dziewas R, Deppe M, Ringelstein EB, Young P . A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects . Mov. Disord. . 25 . 4 . 413–20 . 2010 . 20108356 . 10.1002/mds.22949 . 8667332 .
7. Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A . Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease . Cell . 93 . 6 . 973–83 . 1998 . 9635427 . 10.1016/s0092-8674(00)81203-9. free .
8. König R, Zhou Y, Elleder D, Diamond TL, Bonamy GM, Irelan JT, Chiang CY, Tu BP, De Jesus PD, Lilley CE, Seidel S, Opaluch AM, Caldwell JS, Weitzman MD, Kuhen KL, Bandyopadhyay S, Ideker T, Orth AP, Miraglia LJ, Bushman FD, Young JA, Chanda SK . Global analysis of host-pathogen interactions that regulate early-stage HIV-1 replication . Cell . 135 . 1 . 49–60 . Oct 2008 . 18854154 . 2628946 . 10.1016/j.cell.2008.07.032 .
9. Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC, Mahmoud AB, Ho T, Stewart NA, Rippstein P, Harper ME, Roberts R, Willenborg C, Erdmann J, Pastore A, McBride HM, Langer T, Stewart AF . SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes . Cell Rep . 7 . 3 . 834–47 . 2014 . 24767997 . 10.1016/j.celrep.2014.03.051 . free .
10. Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF . Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance . Brain . 137 . Pt 5 . 1323–36 . 2014 . 24727571 . 3999722 . 10.1093/brain/awu060 .