title: Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation.
abstract: The presynaptic active zone (AZ) is a specialized microdomain designed for the efficient and repetitive release of neurotransmitter. Bassoon and Piccolo are two high molecular weight components of the AZ, with hypothesized roles in its assembly and structural maintenance. However, glutamatergic synapses lacking either protein exhibit relatively minor defects, presumably due to their significant functional redundancy. In the present study, we have used interference RNAs to eliminate both proteins from glutamatergic synapses, and find that they are essential for maintaining synaptic integrity. Loss of Bassoon and Piccolo leads to the aberrant degradation of multiple presynaptic proteins, culminating in synapse degeneration. This phenotype is mediated in part by the E3 ubiquitin ligase Siah1, an interacting partner of Bassoon and Piccolo whose activity is negatively regulated by their conserved zinc finger domains. Our findings demonstrate a novel role for Bassoon and Piccolo as critical regulators of presynaptic ubiquitination and proteostasis.
authors: Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA. cw2622@columbia.edu
authors: Clarissa L
authors: CL
authors: Waites
authors: Sergio A
authors: SA
authors: Leal-Ortiz
authors: Nathan
authors: N
authors: Okerlund
authors: Hannah
authors: H
authors: Dalke
authors: Anna
authors: A
authors: Fejtova
authors: Wilko D
authors: WD
authors: Altrock
authors: Eckart D
authors: ED
authors: Gundelfinger
authors: Craig C
authors: CC
authors: Garner
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*; D016335:Zinc Fingers
chemical_list: C498441:Bsn protein, mouse; C113688:Bsn protein, rat; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C498631:Pclo protein, mouse; C405514:Pclo protein, rat; D044767:Ubiquitin-Protein Ligases
references: J Neurosci. 2011 May 25;31(21):7817-30
references: 21613495
references: Neuron. 2003 Mar 6;37(5):775-86
references: 12628168
references: J Cell Biol. 1992 Oct;119(1):123-37
references: 1527164
references: J Biol Chem. 2002 Mar 22;277(12):10273-82
references: 11786535
references: Trends Biochem Sci. 2005 Jun;30(6):283-6
references: 15950869
references: Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8614-9
references: 15163799
references: Neuron. 2000 Jan;25(1):203-14
references: 10707984
references: J Neurosci. 2009 Apr 8;29(14):4332-45
references: 19357261
references: Neuron. 2000 Jul;27(1):57-69
references: 10939331
references: Annu Rev Neurosci. 2005;28:251-74
references: 16022596
references: Trends Neurosci. 2011 Jun;34(6):326-37
references: 21596448
references: Nat Rev Mol Cell Biol. 2001 Mar;2(3):195-201
references: 11265249
references: J Neurosci. 2010 Feb 3;30(5):1798-809
references: 20130189
references: J Biol Chem. 2008 Dec 12;283(50):34696-703
references: 18818210
references: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5500-5
references: 15064394
references: Annu Rev Cell Dev Biol. 2003;19:141-72
references: 14570567
references: Neuron. 2011 Aug 11;71(3):474-87
references: 21835344
references: J Cell Biol. 2008 Jun 2;181(5):831-46
references: 18519737
references: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6504-9
references: 20332206
references: J Neurosci. 2005 Feb 23;25(8):2002-9
references: 15728840
references: J Neurochem. 2004 Nov;91(4):996-1006
references: 15525353
references: Proteomics. 2008 Sep;8(18):3692-701
references: 18780397
references: Autophagy. 2008 Apr;4(3):372-4
references: 18216494
references: J Neurosci. 2009 Sep 2;29(35):10909-19
references: 19726649
references: Cell Tissue Res. 2006 Nov;326(2):379-91
references: 16865347
references: Results Probl Cell Differ. 2006;43:49-68
references: 17068967
references: J Neurosci. 2006 Nov 1;26(44):11333-41
references: 17079661
references: Mol Cell Neurosci. 2000 May;15(5):417-28
references: 10833299
references: Neuron. 2003 Mar 6;37(5):787-800
references: 12628169
references: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1636-41
references: 20080621
references: Annu Rev Neurosci. 2004;27:223-46
references: 15217332
references: J Biol Chem. 2010 Apr 30;285(18):13507-16
references: 20181957
references: J Neurosci. 1994 Sep;14(9):5223-35
references: 8083732
references: Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17177-82
references: 21903928
references: Nat Rev Neurosci. 2004 May;5(5):385-99
references: 15100721
references: J Biol Chem. 2009 Apr 24;284(17):11706-16
references: 19224863
references: Neuron. 2003 Apr 24;38(2):237-52
references: 12718858
references: J Neurosci. 2010 Mar 3;30(9):3157-66
references: 20203175
references: Neuron. 2010 Nov 18;68(4):724-38
references: 21092861
references: Annu Rev Cell Dev Biol. 2008;24:237-62
references: 18588488
references: Bioessays. 2008 Nov;30(11-12):1075-83
references: 18937340
references: J Comp Neurol. 2009 Jun 20;514(6):641-57
references: 19363811
references: Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17183-8
references: 21903923
references: J Neurosci. 2006 Apr 19;26(16):4277-88
references: 16624948
references: Mol Cell. 2001 May;7(5):927-36
references: 11389840
references: J Neurosci. 2007 Jun 27;27(26):6868-77
references: 17596435
references: J Neurosci. 2011 Oct 5;31(40):14250-63
references: 21976510
references: J Cell Biol. 2005 Feb 28;168(5):825-36
references: 15728193
references: Neuron. 2005 Sep 1;47(5):629-32
references: 16129392
references: Cold Spring Harb Protoc. 2011 Jul 01;2011(7):857-66
references: 21724821
references: Eur J Cell Biol. 1996 Mar;69(3):214-23
references: 8900486
references: Nature. 2001 Jan 25;409(6819):479-84
references: 11206537
references: Methods Enzymol. 1994;228:403-11
references: 7519296
references: Acta Neuropathol. 2009 Sep;118(3):329-47
references: 19597829
references: Neuron. 2010 Nov 18;68(4):710-23
references: 21092860
references: Nat Neurosci. 2003 Mar;6(3):231-42
references: 12577062
references: J Biol Chem. 2005 Oct 7;280(40):34278-87
references: 16085652
references: Traffic. 2008 Jul;9(7):1146-56
references: 18419753