臨床神経学雑誌第48巻第9号
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1 TDP-43 β
2 Table1 Classificationofmotorneurondiseases(motorneurondiseaseofbroad sense) I I I IV ALS(motorneurondiseaseofnarrow sense) 1 SporadicALS Classictype Progressivebulbarpalsy(PBP)type Progressivemuscularatrophy(PMA)type Primarylateralsclerosis(PLS)type ALSwithdementia 2 FamilialALS Autosomal-dominant Cu/Znsuperoxidedesmutase(SOD1)genemutation(ALS1) TDP-43genemutation Non-SOD1,non-TDP-43genemutation Autosomal-recessive Chronicjuveniletypelinkedto2q33alsingene(ALS2) Others 3 WesternPacificALSandparkinsonism-dementiacomplex(ALS/PDC) Guam,K ipeninsula,westnew Guinea Spinobulbarmuscularatrophy(SBMA)orKeneddy-Alter-Sungdisease Androgenreceptorgenemutation Spinalmuscularatrophy(SMA) 1 SMA/NAIPgenemutation SMA-I 2 Others infantiletype(werdnig-hofmanndisease) SMA-I Intermediatetype SMA-I Juveniletype:Kugelberg-Welanaderdisease SMA-IV Adulttype Otherdiseasesinvolvingmainlythemotorsystem PLS(UsualyconvertstoALSfinaly) Familialspasticparaparesis(Usualyincludedinherediraryspinocerebelarataxia) Hirayamadisease(Juvenileunilateralmuscularatrophyoftheupperextremity)
3 Fig.1 Neuronalcytoplasmicinclusions(NCIs)ofthedentategyrusimmunostainedwithantibodiestoTDP-43. A.Antibody to non-phosphorylated TDP-43 immunostainsnotonlythencis(arrow)butalsothenucleusof normalcelswhilethatoftheafectedcelwithanciis unstained. B.Antibody to phosphorylated TDP-43 immunostains thencisonly,andnervecelnucleiareunstained.(courtesyofdrtetsuakiarai) HIV-1 Fig.2 Immunohistochemical findings of inclusions of ALS/FTLD withantibodyagainstphosphorylatedtdp- 43showingdystrophicneurites(a),intranuclearinclusion (b,arrow)andneuronalcytoplasmicinclusions(c).(courtesyofdrtetsuakiarai)
4 Fig.3 Westernblotingpatern(a)anditsschematicdiagram (b)ofthec-terminalfragmentsofphosphorylated TDP-43 of ALS, frontotemporal lobar degeneration (FTLD)withmotorneurondisease(FTLD-MND),FTLD withubiquitininclusions(ftld-u)andftld withprogranulinmutations(mpgrn). Mainbandsare23kDaand24kDa,andthreeadditional weaker bands of18 kda,19 kda and 26 kda are demonstrated.eachdiseasephenotypeshowsthepatern uniquetoit,andnotethatthepaternofthempgrn is theintermediateofftld-u andals.(courtesyofdr MasatoHasegawa) progranulinpgrn valosincontaining proteinvcp PGRN VCP SOD1 SOD1 TDP-43 TDP-43
5 Fig.4 ImmunohistochemistryofanteriorhorncelsofALSoftheK ipeninsuladoubleimmunostainedwithtdp-43(brown)andtau(red) A:TDP-43-positivegranularstructureintheanteriorhorncelbodyandneurites.B:tau-positive neurofibrilarytangles.c:tdp-43-positivecoarsegranulesandroundbody.d:skein-likeinclusions. Table2 Typeclassificationofubiquitin-positiveandTDP-43-positive inclusionsbasedonthepaternofimmunohistochemicalfindings Inclusions(amountandareas) DNIs NCIs N Is type1 superficialcortical 0/ 0/ type2 superficialanddeep 0/ type3 superficialcortical superficialcortical variable type4 neocorticalarea DNs:dystrophicneurites,NCIs:neuronalcytoplasmicinclusions,N Is:neuronal intranuclearinclusions Amountofinclusions.:abundant, :afew,0:none/few
6 Table3 Relationsofclinicalphenotypes,andimmunohistochemicalandmolecularpathologyofFTLD/ALS Tauopathies(FTLD-tau) Pickbody Taugenemutation Othertauopathies Pickdisease FTDP-17 CBD/PSP ALS/PDC ofguam andk i TDP-43proteinopathy(FTLD- U/ALS)andinclusiontypes SD PNFA FTD FTD/ MND sporadicals, TDP-43gene mutationals PGRN gene mutation SOD1gene mutationals Type1(mainlyDNs) Type2(mainlyNCIs) Type3(mainlyDNs& NCIs) Type4(mainlyN Is& NCIs) VCPgenemutation - Non-tauopathy,Non-TDP-43proteinopathy Simpleatrophy DementiaswithfilamentousinclusionsrarelypresentingwithFTLD Alzheimer sdisease,argyrophilicgraindisease,dementiawithlewybodies,parkinson sdisease,multisystem atrophy Abbreviations.CBD:corticobasaldegeneration,FTD:behavioralvariantoffrontotemporaldementia,FTDP-17:frontotemporaldementiawithparkinsonism linkedtochromosome-17,inclusiontypesofdns,ncisandnisarethesameintable2,mnd:motorneurondisease,pgrn:progranulin, PNFA:progressivenon-fluentaphasia,PSP:progressivesupranuclearpalsy,SD:semanticdementia,VCP:valosin-containingprotein TDP-43 TDP- 43 TDP-43 TDP-43 TDP-43
7 TDP-43 progranulin
8 progranulin gene valosin-containing protein gene VCP gene SOD1 SOD1 gene TDP-43 TDP-43 TDP-43 A315T TARDBP
9 TDP-43 gene SOD1 gene
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400 Dementia Japan Vol. 27 No. 4 October 2013 11 9 13 45 14 15 1 : 11 9 14 15 15 15 1 : β β Jorge A Ghiso Departments of Pathology and Psychiatry, New York University School of Medicine, New York, USA
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