title: Cerebellar ataxias: β-III spectrin's interactions suggest common pathogenic pathways.
abstract: Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders all characterised by postural abnormalities, motor deficits and cerebellar degeneration. Animal and in vitro models have revealed β-III spectrin, a cytoskeletal protein present throughout the soma and dendritic tree of cerebellar Purkinje cells, to be required for the maintenance of dendritic architecture and for the trafficking and/or stabilisation of several membrane proteins: ankyrin-R, cell adhesion molecules, metabotropic glutamate receptor-1 (mGluR1), voltage-gated sodium channels (Nav ) and glutamate transporters. This scaffold of interactions connects β-III spectrin to a wide variety of proteins implicated in the pathology of many SCAs. Heterozygous mutations in the gene encoding β-III spectrin (SPTBN2) underlie SCA type-5 whereas homozygous mutations cause spectrin associated autosomal recessive ataxia type-1 (SPARCA1), an infantile form of ataxia with cognitive impairment. Loss-of β-III spectrin function appears to underpin cerebellar dysfunction and degeneration in both diseases resulting in thinner dendrites, excessive dendritic protrusion with loss of planarity, reduced resurgent sodium currents and abnormal glutamatergic neurotransmission. The initial physiological consequences are a decrease in spontaneous activity and excessive excitation, likely to be offsetting each other, but eventually hyperexcitability gives rise to dark cell degeneration and reduced cerebellar output. Similar molecular mechanisms have been implicated for SCA1, 2, 3, 7, 13, 14, 19, 22, 27 and 28, highlighting alterations to intrinsic Purkinje cell activity, dendritic architecture and glutamatergic transmission as possible common mechanisms downstream of various loss-of-function primary genetic defects. A key question for future research is whether similar mechanisms underlie progressive cerebellar decline in normal ageing.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Perkins
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
authors.forename: Daumante
authors.initials: D
authors.lastname: Suminaite
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, EH8 9XD, UK.
authors.forename: Mandy
authors.initials: M
authors.lastname: Jackson
mesh_terms: D000818:Animals; D002524:Cerebellar Ataxia / Q000235:genetics / Q000503:physiopathology*; D060825:Cognitive Dysfunction / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D009154:Mutation; D013049:Spectrin / Q000235:genetics / Q000502:physiology*
chemical_list: C495133:SPTBN2 protein, human; D013049:Spectrin
references.citation: Hum Mol Genet. 2012 Dec 15;21(26):5472-83
references.pmid: 23001565
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6022-7
references.pmid: 20231455
references.citation: Neuroreport. 2003 May 6;14(6):841-5
references.pmid: 12858044
references.citation: Mov Disord. 2006 Mar;21(3):396-401
references.pmid: 16211615
references.citation: Cerebellum. 2015 Feb;14(1):8-11
references.pmid: 25255716
references.citation: J Physiol. 2005 Nov 15;569(Pt 1):179-93
references.pmid: 16166153
references.citation: Eur J Paediatr Neurol. 2014 May;18(3):413-5
references.pmid: 24252256
references.citation: J Cell Biol. 1991 Sep;114(6):1233-41
references.pmid: 1716634
references.citation: PLoS One. 2012;7(6):e37599
references.pmid: 22723836
references.citation: Science. 2000 Oct 27;290(5492):739-44
references.pmid: 11052929
references.citation: Neurobiol Dis. 2009 Jan;33(1):81-8
references.pmid: 18930825
references.citation: Biol Psychiatry. 2008 Jul 15;64(2):81-8
references.pmid: 18395701
references.citation: Nat Genet. 2006 Apr;38(4):447-51
references.pmid: 16501573
references.citation: Aging Cell. 2010 Oct;9(5):722-35
references.pmid: 20569241
references.citation: Neuron. 1997 Oct;19(4):881-91
references.pmid: 9354334
references.citation: J Biol Chem. 2000 Feb 18;275(7):4834-9
references.pmid: 10671518
references.citation: J Hum Genet. 2014 Oct;59(10):569-73
references.pmid: 25142508
references.citation: Eur J Hum Genet. 2014 Feb;22(2):286-8
references.pmid: 23838597
references.citation: J Neurosci. 2011 Nov 16;31(46):16581-90
references.pmid: 22090485
references.citation: Nat Genet. 1999 Dec;23(4):391-2
references.pmid: 10581021
references.citation: J Neuroimmune Pharmacol. 2013 Dec;8(5):1098-105
references.pmid: 23709339
references.citation: Cerebellum. 2008;7(4):505-16
references.pmid: 18855093
references.citation: PLoS Genet. 2007 Jun;3(6):e108
references.pmid: 17590087
references.citation: Cerebellum. 2014 Feb;13(1):29-41
references.pmid: 23955261
references.citation: J Med Genet. 2014 Sep;51(9):590-5
references.pmid: 25062847
references.citation: Alcohol. 2005 Jan;35(1):67-73
references.pmid: 15922139
references.citation: J Clin Invest. 2004 Feb;113(4):582-90
references.pmid: 14966567
references.citation: Nat Genet. 1997 Jan;15(1):62-9
references.pmid: 8988170
references.citation: Nature. 2001 Mar 1;410(6824):89-93
references.pmid: 11242047
references.citation: J Psychiatry Neurosci. 2005 May;30(3):178-86
references.pmid: 15944742
references.citation: J Neurosci. 2009 Jul 22;29(29):9244-54
references.pmid: 19625515
references.citation: Nat Genet. 1997 Sep;17(1):65-70
references.pmid: 9288099
references.citation: J Biol Chem. 2001 Sep 28;276(39):36598-605
references.pmid: 11461920
references.citation: J Neurosci. 2007 Oct 31;27(44):12033-44
references.pmid: 17978045
references.citation: J Neurol. 2007 Dec;254(12):1649-52
references.pmid: 17940722
references.citation: Am J Hum Genet. 2003 Apr;72(4):839-49
references.pmid: 12644968
references.citation: Ann Neurol. 2012 Dec;72(6):870-80
references.pmid: 23280838
references.citation: Nat Genet. 2000 Oct;26(2):191-4
references.pmid: 11017075
references.citation: Neurogenetics. 2015 Jul;16(3):233-6
references.pmid: 25566820
references.citation: J Med Genet. 2008 Jan;45(1):32-5
references.pmid: 17932120
references.citation: J Child Neurol. 2013 Oct;28(10):1292-5
references.pmid: 22914369
references.citation: Neurology. 2004 Jan 27;62(2):327-9
references.pmid: 14745083
references.citation: Nat Genet. 1994 Nov;8(3):221-8
references.pmid: 7874163
references.citation: Cerebellum. 2013 Apr;12(2):162-4
references.pmid: 22843192
references.citation: Cortex. 2011 Jan;47(1):101-16
references.pmid: 20060110
references.citation: Am J Hum Genet. 2010 Nov 12;87(5):593-603
references.pmid: 21035104
references.citation: Hum Mol Genet. 2010 Sep 15;19(18):3634-41
references.pmid: 20603325
references.citation: Orphanet J Rare Dis. 2012 Sep 17;7:67
references.pmid: 22986007
references.citation: Hum Mol Genet. 2004 Oct 15;13(20):2535-43
references.pmid: 15317756
references.citation: J Neurosci. 2014 Jul 23;34(30):9891-904
references.pmid: 25057192
references.citation: Neurology. 1999 Oct 12;53(6):1355-7
references.pmid: 10522902
references.citation: J Neurosci. 2011 Sep 7;31(36):13002-14
references.pmid: 21900579
references.citation: Neuroreport. 1996 Aug 12;7(12):2013-7
references.pmid: 8905715
references.citation: Nat Neurosci. 2006 Oct;9(10):1302-11
references.pmid: 16936724
references.citation: Neuron. 2002 Jul 3;35(1):25-38
references.pmid: 12123606
references.citation: Neurology. 2014 Oct 21;83(17):1554-61
references.pmid: 25253745
references.citation: J Neurosci. 2011 Aug 17;31(33):11795-807
references.pmid: 21849540
references.citation: J Neurosci. 2007 Oct 10;27(41):11065-74
references.pmid: 17928448
references.citation: Nat Genet. 1996 Nov;14(3):269-76
references.pmid: 8896555
references.citation: Nat Genet. 1996 Nov;14(3):277-84
references.pmid: 8896556
references.citation: Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18733-8
references.pmid: 25512503
references.citation: Cerebellum. 2014 Jun;13(3):331-7
references.pmid: 24272953
references.citation: Nat Genet. 2010 Apr;42(4):313-21
references.pmid: 20208537
references.citation: Brain. 2010 Dec;133(Pt 12):3510-8
references.pmid: 21106500
references.citation: Hum Mol Genet. 2014 Jul 15;23(14):3875-82
references.pmid: 24603075
references.citation: Neuron. 1997 Sep;19(3):665-78
references.pmid: 9331356
references.citation: PLoS Genet. 2012;8(12):e1003074
references.pmid: 23236289
references.citation: Neurology. 2005 Aug 23;65(4):529-34
references.pmid: 16116111
references.citation: Eur J Hum Genet. 2005 Jan;13(1):118-20
references.pmid: 15470364
references.citation: Neurochem Res. 2012 Mar;37(3):480-6
references.pmid: 22037840
references.citation: J Neurosci. 1998 May 15;18(10):3606-19
references.pmid: 9570792
references.citation: Neurobiol Dis. 2009 Feb;33(2):260-73
references.pmid: 19041943
references.citation: Eur J Pharmacol. 2007 Feb 28;557(2-3):106-14
references.pmid: 17188264
references.citation: Cell. 2012 Nov 9;151(4):847-58
references.pmid: 23141541
references.citation: BMC Genet. 2012 Jul 10;13:55
references.pmid: 22781464
references.citation: Brain. 2004 Dec;127(Pt 12):2572-83
references.pmid: 15329353
references.citation: Psychiatr Danub. 2013 Sep;25(3):221-6
references.pmid: 24048388
references.citation: J Neurosci. 2015 Apr 29;35(17):6752-69
references.pmid: 25926453
references.citation: Hum Mol Genet. 2001 Jul 1;10(14):1441-8
references.pmid: 11448935
references.citation: J Comp Neurol. 1988 Aug 8;274(2):168-77
references.pmid: 3209740
references.citation: Neuroepidemiology. 2014;42(3):174-83
references.pmid: 24603320
references.citation: Curr Biol. 2005 May 24;15(10):918-28
references.pmid: 15916948
references.citation: Brain. 2015 Jul;138(Pt 7):1817-32
references.pmid: 25981959
references.citation: Brain. 1998 Apr;121 ( Pt 4):561-79
references.pmid: 9577385
references.citation: Am J Hum Genet. 2009 Nov;85(5):544-57
references.pmid: 19878914
references.citation: Am J Hum Genet. 2011 Jul 15;89(1):121-30
references.pmid: 21683323
references.citation: Dement Geriatr Cogn Disord. 2001 May-Jun;12(3):211-8
references.pmid: 11244215
references.citation: Nat Genet. 1994 Nov;8(3):280-4
references.pmid: 7874171
references.citation: Lancet. 1994 Jan 1;343(8888):63-4
references.pmid: 7905084
references.citation: J Neurosci. 2008 Apr 30;28(18):4640-8
references.pmid: 18448641
references.citation: J Neurol. 2013 Jul;260(7):1807-12
references.pmid: 23471613
references.citation: Hum Mol Genet. 2013 Jan 15;22(2):271-83
references.pmid: 23087021
references.citation: J Clin Invest. 2015 Jan;125(1):263-74
references.pmid: 25485680
references.citation: J Cell Biol. 1998 Jul 27;142(2):485-97
references.pmid: 9679146
references.citation: Nat Neurosci. 2000 Feb;3(2):157-63
references.pmid: 10649571
references.citation: Cerebellum. 2008;7(3):406-16
references.pmid: 18587625
references.citation: J Neurosci. 2010 Apr 7;30(14):4857-67
references.pmid: 20371805
references.citation: J Cell Biol. 2010 Apr 5;189(1):143-58
references.pmid: 20368622
references.citation: Nat Genet. 1996 Nov;14(3):285-91
references.pmid: 8896557
references.citation: J Physiol. 2014 Jan 1;592(1):229-47
references.pmid: 24218544
references.citation: PLoS One. 2011;6(5):e20035
references.pmid: 21637831
references.citation: J Neurosci. 2003 Jun 15;23(12):4899-912
references.pmid: 12832512
references.citation: J Neurosci. 1997 Jun 15;17(12):4517-26
references.pmid: 9169512
references.citation: Arch Neurol. 2009 Jan;66(1):97-101
references.pmid: 19139306
references.citation: Nat Genet. 2007 Dec;39(12):1434-6
references.pmid: 18037885
references.citation: Nat Neurosci. 2005 Oct;8(10 ):1329-34
references.pmid: 16136036
references.citation: Anat Sci Int. 2011 Mar;86(1):10-8
references.pmid: 21153457
references.citation: Nat Genet. 2006 Feb;38(2):184-90
references.pmid: 16429157
references.citation: J Neurobiol. 2005 Jul;64(1):75-90
references.pmid: 15884003
references.citation: Am J Hum Genet. 2003 Jan;72(1):191-9
references.pmid: 12489043
references.citation: Elife. 2014 Sep 30;3:e04193
references.pmid: 25269146
references.citation: Nat Genet. 1999 Apr;21(4):379-84
references.pmid: 10192387
references.citation: Nat Genet. 1993 Jul;4(3):221-6
references.pmid: 8358429
references.citation: Eur J Paediatr Neurol. 2015 Mar;19(2):271-3
references.pmid: 25530029
references.citation: Ann Neurol. 2012 Dec;72(6):859-69
references.pmid: 23280837