SomȱförȱavläggandeȱavȱmedicineȱdoktorsexamenȱvidȱSahlgrenskaȱakademinȱvidȱGöteborgsȱuniversitetȱ kommerȱattȱoffentligenȱförsvarasȱiȱhörsalȱKammaren,ȱSU/Sahlgrenska,ȱGöteborgȱ

—•…‡’–‹„‹Ž‹–›‰‡‡•‹…‘ˆ‘”ƒ–‹‘ƒŽ†‹•‡ƒ•‡•

Akademiskȱavhandlingȱ ȱ

SomȱförȱavläggandeȱavȱmedicineȱdoktorsexamenȱvidȱSahlgrenskaȱakademinȱvidȱGöteborgsȱuniversitetȱ kommerȱattȱoffentligenȱförsvarasȱiȱhörsalȱKammaren,ȱSU/Sahlgrenska,ȱGöteborgȱ

Fredagenȱdenȱ27ȱnovemberȱ2009,ȱkl.ȱ09.00ȱ avȱ

     ȱ

Fakultetsopponent:ȱDocentȱMikkoȱHiltunenȱ DepartmentȱofȱNeurology,ȱUniversityȱofȱKuopio,ȱFinlandȱ

ȱ

Avhandlingenȱbaserasȱpåȱföljandeȱarbeten:ȱ

I. Malinȱ E.ȱ Andersson*ȱ Annicaȱ Sjölander,ȱ Nielsȱ Andreasen,ȱ Lennartȱ Minthon,ȱ Oskarȱ Hansson,ȱNenadȱBogdanovic,ȱChristinaȱJern,ȱKatarinaȱJood,ȱAndersȱWallin,ȱKajȱBlenȬ now,ȱHenrikȱZetterberg.ȱKinesinȱgeneȱvariabilityȱaffectsȱtauȱphosphorylationȱinȱearlyȱAlzȬ heimer’sȱdisease.ȱTheȱInternationalȱJournalȱofȱMolecularȱMedicine.ȱ2007,ȱ20:ȱ233Ȭ239.ȱ II. MalinȱE.ȱAndersson*,ȱMadeleineȱZetterberg,ȱGunnarȱTasa,ȱMonaȱSeibtȱPalmér,ȱErkkiȱ

Juronen,ȱ Paitȱ Teesalu,ȱ Kajȱ Blennow,ȱ Henrikȱ Zetterberg.ȱ Variabilityȱ inȱ theȱ kinesinȱ lightȱ chainȱ1ȱgeneȱmayȱinfluenceȱriskȱofȱageȬrelatedȱcataract.ȱMolecularȱVision.ȱ2007,ȱ13:ȱ993Ȭ996.ȱ III. Malinȱ vonȱ Otter,ȱ Saraȱ Landgren,ȱ Staffanȱ Nilsson,ȱ Carolineȱ Lundvall,ȱ Lennartȱ MinȬ

thon,ȱ Nenadȱ Bogdanovic,ȱ Nielsȱ Andreasen,ȱ Deborahȱ R.ȱ Gustafson,ȱ Ingemarȱ Skoog,ȱ Andersȱ Wallin,ȱ Annaȱ Håkansson,ȱ Hansȱ Nissbrandt,ȱ Madeleineȱ Zetterberg,ȱ Gunnarȱ Tasa,ȱKajȱBlennow,ȱHenrikȱZetterberg.ȱKinesinȱlightȱchainȱ1ȱgeneȱhaplotypesȱinȱthreeȱconȬ formationalȱdisorders.ȱAcceptedȱforȱpublicationȱinȱNeuroMolecularȱMedicine,ȱOctȱ2009.ȱ IV. Malinȱ vonȱ Otter

,ȱ Saraȱ Landgren

,ȱ Staffanȱ Nilsson,ȱ Draganaȱ Celojevic,ȱ Petraȱ

Bergström,ȱ Annaȱ Håkansson,ȱ Hansȱ Nissbrandt,ȱ Marekȱ Drozdzik,ȱ Monikaȱ Bialecka,ȱ MateuszȱKurzawski,ȱKajȱBlennow,ȱMichaelȱNilsson,ȱOlaȱHammarsten,ȱHenrikȱZetterȬ berg.ȱAssociationȱofȱNrf2ȬencodingȱNFE2L2ȱhaplotypesȱwithȱParkinson’sȱdisease.ȱSubmittedȱ manuscript,ȱJuneȱ2009.ȱ

V. MalinȱvonȱOtter,ȱSaraȱLandgren,ȱStaffanȱNilsson,ȱMadeleineȱZetterberg,ȱDraganaȱCeȬ lojevic,ȱ Petraȱ Bergström,ȱ Lennartȱ Minthon,ȱ Nenadȱ Bogdanovic,ȱ Nielsȱ Andreasen,ȱ Deborahȱ R.ȱ Gustafson,ȱ Ingmarȱ Skoog,ȱ Andersȱ Wallin,ȱ Gunnarȱ Tasa,ȱ Kajȱ Blennow,ȱ Michaelȱ Nilsson,ȱ Olaȱ Hammarsten,ȱ Henrikȱ Zetterberg.ȱ Nrf2Ȭencodingȱ NFE2L2ȱ haploȬ typesȱ influenceȱ diseaseȱ progressionȱ butȱ notȱ riskȱ inȱ Alzheimer’sȱ diseaseȱ andȱ ageȬrelatedȱ cataȬ ract.ȱSubmittedȱmanuscript,ȱSeptȱ2009.ȱ

*Artiklarȱpubliceradeȱföreȱjuliȱ2009ȱpubliceradesȱiȱnamnetȱMalinȱE.ȱAnderssonȱ

§

Dessaȱförfattareȱbidrogȱlikvärdigtȱtillȱdennaȱartikelȱ

—•…‡’–‹„‹Ž‹–›‰‡‡•‹…‘ˆ‘”ƒ–‹‘ƒŽ†‹•‡ƒ•‡•

    

DepartmentȱofȱPsychiatryȱandȱNeurochemistry,ȱInstituteȱofȱNeuroscienceȱandȱPhysiology,ȱ UniversityȱofȱGothenburg,ȱGothenburg,ȱSweden,ȱ2009ȱ

ȱ ȱ Abstractȱ

Conformationalȱ diseasesȱ areȱ characterizedȱ byȱ proteinȱ misfoldingȱ andȱ aggregationȱ inȱ theȱ affectedȱtissue.ȱTheȱaimȱofȱthisȱthesisȱwasȱtoȱfindȱgeneticȱsupportȱforȱmechanismsȱinȱcommonȱ forȱ threeȱ prevalentȱ conformationalȱ diseases:ȱ Alzheimer’sȱ diseaseȱ (AD),ȱ Parkinson’sȱ diseaseȱ (PD)ȱandȱcataract.ȱ

Theȱ influenceȱ ofȱ geneticȱ variabilityȱ inȱ candidateȱ genesȱ hypothesizedȱtoȱ beȱ involvedȱ inȱ proȬ teinȱaggregationȱwasȱinvestigatedȱforȱassociationȱwithȱriskȱofȱtheȱsporadicȱformsȱofȱAD,ȱPDȱ andȱ cataract.ȱ Furthermore,ȱ analysisȱofȱ associationȱ withȱ ageȱatȱ onsetȱ (AAO)ȱ ofȱ disease,ȱ and,ȱ forȱ AD,ȱ associationȱ withȱ miniȬmentalȱ stateȱ examinationȱ (MMSE)ȱ scoresȱ andȱ levelsȱ ofȱ theȱ cerebrospinalȱfluidȱ(CSF)ȱbiomarkers:ȱAΆ

ȱ(theȱ42ȱaminoȱacidȱformȱofȱamyloidȱΆ),ȱTȬtauȱ(totalȱ tau,ȱ i.e.ȱ allȱ isoformsȱ ofȱ tau)ȱ andȱ PȬtau

ȱ (hyperphosphorylatedȱ tauȱ proteinȱ asȱ measuredȱ byȱ phosphorylationȱonȱaminoȱacidȱ181)ȱwasȱcarriedȱout.ȱ

Theȱkinesinȱproteinȱisȱimportantȱforȱmaintainingȱcellȱshapeȱandȱfunction,ȱespeciallyȱinȱelonȬ gatedȱ cellsȱ suchȱ asȱ neuronsȱ andȱ lensȱ cells.ȱ Previousȱ molecularȱ andȱ geneticȱ studiesȱ supportȱ impairedȱkinesinȬmediatedȱtransportȱasȱaȱpotentialȱcontributorȱinȱAD,ȱPDȱandȱcataract.ȱWeȱ analysedȱtheȱcontributionȱofȱvariationȱinȱtheȱkinesinȱlightȱchainȱ1ȱgeneȱ(KLC1)ȱencodingȱtheȱ kinesinȱlightȱchainȱproteinȱ1ȱproteinȱ(KLC1),ȱinitiallyȱbyȱusingȱaȱsingleȱnucleotideȱpolymorȬ phismȱ(SNP)ȱapproachȱ(paperȱIȱandȱII)ȱandȱlaterȱinȱaȱhaplotypeȱstudyȱ(paperȱIII).ȱAltogether,ȱ withȱ theȱ possibleȱ exceptionȱ forȱ cataract,ȱ theȱ resultsȱ ofȱ theseȱ papersȱ doȱ notȱ supportȱ geneticȱ influenceȱofȱKLC1ȱonȱriskȱofȱdisease.ȱ

Oxidativeȱ stressȱ isȱ aȱ contributingȱ factorȱ toȱ agingȱ andȱ degenerativeȱ diseases.ȱ Theȱ proteinsȱ Nrf2ȱ (nuclearȱ factorȱ (erythroidȬderivedȱ 2)Ȭlikeȱ 2)ȱ andȱ Keap1ȱ (KelchȬlikeȱ ECHȬassociatedȱ proteinȱ1),ȱconstituteȱtheȱtwoȱmainȱregulatorsȱofȱtheȱinducedȱcellularȱoxidativeȱstressȱdefenseȱ calledȱ theȱ phaseȱ IIȱ response.ȱ Inȱ paperȱ IVȱ andȱ Vȱ weȱ investigatedȱ theirȱ respectiveȱ genesȱ NFE2L2ȱ(Nuclearȱfactorȱ(erythroidȬderivedȱ2)Ȭlikeȱ2)ȱandȱKEAP1ȱ(KelchȬlikeȱECHȬassociatedȱ proteinȱ1)ȱasȱpossibleȱsusceptibilityȱgenesȱinȱAD,ȱPDȱandȱcataract.ȱWeȱfoundȱthatȱvariationȱinȱ oneȱNFE2L2ȱhaplotypeȱwindow,ȱwhichȱisȱinȱLDȱwithȱfunctionalȱpromoterȱpolymorphismsȱinȱ theȱ sameȱ gene,ȱ wasȱ associatedȱ withȱ riskȱ ofȱ PDȱ inȱ twoȱ independentȱ Europeanȱ caseȬcontrolȱ materialsȱ (paperȱ IV).ȱ Inȱ ADȱ andȱ cataract,ȱ variationȱ inȱ theȱ sameȱ haplotypeȱ windowȱ wasȱ associatedȱ withȱ AAOȱ ofȱ theȱ diseasesȱ (paperȱ V).ȱ Noȱ associationȱ ofȱ KEAP1ȱ withȱ anyȱ ofȱ theȱ studiedȱdiseasesȱwasȱfound.ȱ

TheȱmajorȱfindingȱofȱthisȱthesisȱwasȱtheȱidentificationȱofȱNFE2L2ȱasȱaȱpotentialȱsusceptibilityȱ geneȱinȱPDȱaddingȱgeneticȱsupportȱtoȱcurrentȱindicationsȱthatȱNrf2ȱmayȱhaveȱanȱimportantȱ functionȱinȱtheȱcellularȱdefenseȱagainstȱPD.ȱ

Keywords:ȱConformationalȱdisease,ȱAlzheimer’sȱdisease,ȱParkinson’sȱdisease,ȱcataract,ȱproteinȱ aggregation,ȱcellularȱtransport,ȱoxidativeȱstress,ȱsusceptibilityȱgenes,ȱSNP,ȱhaplotypeȱ

ISBNȱ978Ȭ91Ȭ628Ȭ7936Ȭ5ȱ