title: The effect of HSP-causing mutations in SPG3A and NIPA1 on the assembly, trafficking, and interaction between atlastin-1 and NIPA1.
abstract: Despite its genetic heterogeneity, hereditary spastic paraplegia (HSP) is characterized by similar clinical phenotypes, suggesting that a common biochemical pathway underlies its pathogenesis. In support of this hypothesis, we used a combination of immunoprecipitation, confocal microscopy, and flow cytometry to demonstrate that two HSP-associated proteins, atlastin-1 and NIPA1, are direct binding partners, and interestingly, that the endogenous expression and trafficking of these proteins is highly dependent upon their coexpression. In addition, we demonstrated that the cellular distribution of atlastin-1:NIPA1 complexes was dramatically altered by HSP-causing mutations, as missense mutations in atlastin-1 (R239C and R495W) and NIPA1 (T45R and G106R) caused protein sequestration in the Golgi complex (GC) and endoplasmic reticulum (ER), respectively. Moreover, we demonstrated that HSP-causing mutations in both atlastin-1 and NIPA1 reduced axonal and dendritic sprouting in cultured rat cortical neurons. Together, these findings support the hypothesis that NIPA1 and atlastin-1 are members of a common biochemical pathway that supports axonal maintenance, which may explain in part the characteristic degeneration of long spinal pathways observed in patients with HSP.
authors.affiliation: Medical Scientist Training Program, Vanderbilt University, Nashville, TN 37232-8552, USA.
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Botzolakis
authors.forename: Jiali
authors.initials: J
authors.lastname: Zhao
authors.forename: Katharine N
authors.initials: KN
authors.lastname: Gurba
authors.forename: Robert L
authors.initials: RL
authors.lastname: Macdonald
authors.forename: Peter
authors.initials: P
authors.lastname: Hedera
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C478824:NIPA1 protein, human; C559128:NIPA1 protein, rat; D011993:Recombinant Fusion Proteins; C513123:Atl1 protein, rat; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins
references.citation: Am J Hum Genet. 2003 Oct;73(4):967-71
references.pmid: 14508710
references.citation: Nature. 2009 Aug 20;460(7258):978-83
references.pmid: 19633650
references.citation: Nat Neurosci. 2007 Feb;10(2):177-85
references.pmid: 17220882
references.citation: J Med Genet. 2003 Feb;40(2):81-6
references.pmid: 12566514
references.citation: J Neurosci. 2008 Dec 17;28(51):13938-51
references.pmid: 19091982
references.citation: Neuroradiology. 2005 Oct;47(10):730-4
references.pmid: 16143870
references.citation: Nat Genet. 1999 Nov;23(3):296-303
references.pmid: 10610178
references.citation: Lancet Neurol. 2008 Dec;7(12):1127-38
references.pmid: 19007737
references.citation: J Biol Chem. 2010 Aug 20;285(34):26390-405
references.pmid: 20551311
references.citation: Proc Natl Acad Sci U S A. 2006 Jul 11;103(28):10666-71
references.pmid: 16815977
references.citation: J Neuropathol Exp Neurol. 2003 Nov;62(11):1166-77
references.pmid: 14656074
references.citation: Arch Neurol. 2004 Dec;61(12):1867-72
references.pmid: 15596607
references.citation: Hum Mutat. 2005 Feb;25(2):135-41
references.pmid: 15643603
references.citation: J Clin Invest. 2010 Apr;120(4):1097-110
references.pmid: 20200447
references.citation: Mov Disord. 2006 Sep;21(9):1531-3
references.pmid: 16795073
references.citation: Hum Mol Genet. 2009 Oct 15;18(20):3805-21
references.pmid: 19620182
references.citation: Nat Genet. 2001 Nov;29(3):326-31
references.pmid: 11685207
references.citation: Neurology. 2002 Dec 24;59(12):2002-5
references.pmid: 12499504
references.citation: Dev Biol. 2009 Jun 15;330(2):250-62
references.pmid: 19341724
references.citation: J Biol Chem. 2003 Dec 5;278(49):49063-71
references.pmid: 14506257
references.citation: Curr Neurol Neurosci Rep. 2006 Jan;6(1):65-76
references.pmid: 16469273
references.citation: Neurogenetics. 2004 Dec;5(4):239-43
references.pmid: 15517445
references.citation: J Biol Chem. 2007 Mar 16;282(11):8060-8
references.pmid: 17166836
references.citation: Hum Mol Genet. 2002 Jan 15;11(2):153-63
references.pmid: 11809724
references.citation: Hum Mol Genet. 2008 Jun 1;17(11):1591-604
references.pmid: 18270207
references.citation: Neurogenetics. 2005 May;6(2):79-84
references.pmid: 15711826
references.citation: Hum Mol Genet. 2006 Apr 15;15(8):1343-53
references.pmid: 16537571
references.citation: Pharmacol Ther. 2006 Jan;109(1-2):42-56
references.pmid: 16005518
references.citation: Mol Cell Neurosci. 2007 May;35(1):1-13
references.pmid: 17321752
references.citation: Semin Neurol. 1999;19(3):301-9
references.pmid: 12194386
references.citation: Arch Neurol. 2004 Oct;61(10):1600-3
references.pmid: 15477516
references.citation: Nat Rev Mol Cell Biol. 2004 Feb;5(2):133-47
references.pmid: 15040446
references.citation: Nat Genet. 2002 Aug;31(4):347-8
references.pmid: 12134148
references.citation: J Biol Chem. 2008 Oct 31;283(44):29740-52
references.pmid: 18723504
references.citation: Hum Mutat. 2004 Jan;23(1):98
references.pmid: 14695538
references.citation: Neuropathol Appl Neurobiol. 2004 Dec;30(6):576-84
references.pmid: 15540998
references.citation: Hum Mol Genet. 2006 Jan 15;15(2):307-18
references.pmid: 16339213
references.citation: Expert Opin Pharmacother. 2007 Jul;8(10):1433-9
references.pmid: 17661726
references.citation: Cell. 2009 Aug 7;138(3):549-61
references.pmid: 19665976
references.citation: Am J Hum Genet. 2003 Nov;73(5):1147-56
references.pmid: 14564668