Table Of ContentResearch and Perspectives in Alzheimer’s Disease
P. H.St.George-Hyslop
W. C. Mobley · Y. Christen (Eds.)
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POUR LA RECHERCHE
1 23 THERAPEUTIQUE
Intracellular Traffic and Neurodegenerative
Disorders
RESEARCH AND PERSPECTIVES IN ALZHEIMER’SDISEASE
Peter H. St. George-Hyslop • William C. Mobley
Yves Christen
Editors
Intracellular Traffic
and Neurodegenerative
Disorders
123
Editors
Dr.PeterH.St.George-Hyslop Dr.WilliamC.Mobley
DepartmentofLaboratoryMedicine DepartmentofNeurology
andPathobiology StandfordUniversitySchoolofMedicine
UniversityofToronto StandfordCA94305-5316
TranzNeuroscienceBldg. USA
TorontoONM5S3H2 [email protected]
Canada
[email protected]
Dr.YvesChristen
FondationIPSEN
PourlaRechercheThérapeutique
65,quaiGeorgesGorse
92650BoulogneBillancourt
Cedex-France
[email protected]
ISSN0945-6066
ISBN978-3-540-87940-4 e-ISBN978-3-540-87941-1
LibraryofCongressControlNumber:2008936139
(cid:2)c 2009Springer-VerlagBerlinHeidelberg
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Foreword
Neurodegenerative disorders are common and devastating. Rationally, the most
effective treatments will target pathogenetic mechanisms. While alternative ap-
proaches, based on alleviating the symptoms of patients with Alzheimer disease,
Parkinsondisease,Huntingtondisease,priondisordersoramyotrophiclateralscle-
rosis, can be expected to reduce suffering, studies of pathogenesis of these age-
relateddisorderswillbemostimportantforenablingearlydiagnosisandthecreation
of preventative and curative treatments. It is in this context that a recent IPSEN
meeting (The 23rd Colloque Me´decine et Recherche, April 28, 2008) focused on
arolefordisruptionofintracellulartraffickinginneurodegenerativedisorders.The
meetingcapturedemerginginsightsintopathogenesisfromdisruptedtraffickingand
processingofproteinsimplicatedinage-relateddegeneration.
Protein folding, trafficking and signaling were the principal topics covered at
the meeting. Importantly,the presenters pointed to the importantlyintersection of
these themes. While the proteolytic processing of APP into its toxic product, the
Aβpeptide,isanintensivefocusofworkinmanylaboratories,itisonlyrelatively
recentlythatinvestigatorshavebeguntoexamineindepththecellularcompartments
and traffickingevents that mediate APP processing and how derangementof traf-
ficking pathways could impact them. Thus, discoveries by St George-Hyslop and
colleaguesthatSORL1bindsAPP,thatcertainpolymorphismsinSORL1increases
theriskofAlzheimerdiseaseandthatseveralofthesepolymorphismsarepredicted
tomodifySORL1 levelsso asto increaseAβ productionprovidedthe perspective
that malfunctionof cellular mechanismscould play a defining role in APP-linked
pathology. Willnow built on this theme by defining further the cellular pathways
impactedbySORLA,whileSeamanlinkedtheseobservationswithproteinsofthe
retromercomplex,forwhichearlierevidencesuggesteda linktoalteredAPPpro-
cessing. ContributionsbyBeyreutherandKins and byHaass furtherinformedthe
discussion by providing new insights into the proteins with which APP interacts,
including its family members APLP1 and 2, and through studies of g secretase.
GandyreviewedstudiesshowingthatAPPsortingandmetabolismisinformedby
a numberofextracellularsignalsthatactthroughphosphorylationof APP. Impor-
tantly,theparticipationoftheendosomalpathwayandearlyendosomesinparticular
v
vi Foreword
reinforce the view that trafficking errors at this locus contribute significantly to
APP-linked pathology,observationsaddressed directly by Rajendran and Simons.
Sorkindetailed recentadvancesin understandingproteintraffickingand signaling
in the endosomal system, studies that must now be extended to APP. But what is
itaboutAPPmisprocessingthatdefineskeystepsinpathogenesis?Mostinvestiga-
torsfocussquarelyonAβ,butrecentfindingssuggestthatamorerefinedfocuson
APPwillbeneededtounderstandimportantsteps.Indeed,Mobleyandcolleagues,
in studies of mouse models of Down syndrome, show that APP gene dose, and
particularlythe levelsof its C-terminalfragments,may be more directlylinked to
Alzheimer-likepathogenesisthantheleveloftheAβpeptide.Bywhatmechanisms
wouldaltered traffickingmechanismsinfluencethe cell? An emergingtheme, one
thatlinksstudiesofAlzheimerpathogenesistootherneurodegenerativedisorders,is
thatproteinmisfoldingplaysadefiningrole.Thiswasthefocusofworkreportedby
Lindquist,instudiesofParkinsonandHuntingtondiseasemodels,andMandelkow
andcolleaguesinstudiesoftaumutants.Theabilityofmisfoldedproteinstodysreg-
ulatecellularprocessesraisestheexcitingpossibilitythatproteinmisfoldingerrors
can be defined and serve as a target of future therapeutics. In the end, it will be
essentialtoexploretheeventswhosecompromiseiscriticaltoneuralcellsurvival
andfunction.Oneimportantlesionmaybetheaxonaltransportoftrophicmessages.
Holzbauermakesacompellingcasethatsuchmessagesaremarkedlycompromised
inmodelsofamyotrophiclateralsclerosisandSaudoudocumentsdramaticchanges
inBDNFtraffickinginmodelsofHuntingtondisease.Finally,Mobleyreportsdis-
ruptionofNGFtransportinmodelsofDownsyndromeandAlzheimerdisease.That
otherimportantretrogrademessagesmustbeexaminedissuggestedbyMartinand
colleagues who document the dynamic processes that link axonal transport with
synapticplasticity.
Thoughitisdifficulttopredictthecourseoffuturework,themeetingsupported
the view that misregulation of processing and trafficking events, especially those
thatoccurin theendocyticpathway,willbeimportantfordefiningandcountering
thepathogenesisofage-relatedneurodegenerativedisorders.
W.Mobley
P.StGeorge-Hyslop
Y.Christen
Acknowledgements
The editors wish to thank Jacqueline Mervaillie and Sonia Le Cornec for the
organizationofthemeetingandMaryLynnGagefortheeditingofthebook.
vii
Contents
Contributors....................................................... xi
AmyloidPrecursorProteinSorting andProcessing: Transmitters,
Hormones,andProteinPhosphorylationMechanisms................. 1
SamGandy,OdetedaCruzeSilva,EdgardaCruzeSilva,
ToshiharuSuzuki,MichelleEhrlich,andScottSmall
IntramembraneProteolysisbyγ-SecretaseandSignalPeptidePeptidases 11
ReginaFluhrerandChristianHaass
AxonalTransportandNeurodegenerativeDisease .................... 27
ErikaL.F.Holzbaur
SimpleCellularSolutionstoComplexProblems...................... 41
SusanLindquistandKarenL.Allendoerfer
TauandIntracellularTransportinNeurons ......................... 59
E.-M.Mandelkow,E.Thies,S.Konzack,andE.Mandelkow
SignalingBetweenSynapseandNucleusDuringSynapticPlasticity ..... 71
Kwok-OnLai,DanWang,andKelseyC.Martin
Axonal Transport of Neurotrophic Signals: An Achilles’ Heel
forNeurodegeneration? .......................................... 87
AhmadSalehi,ChengbiaoWu,KeZhan,andWilliamC.Mobley
MembraneTraffickingandTargetinginAlzheimer’sDisease........... 103
LawrenceRajendranandKaiSimons
Huntington’s Disease: Function and Dysfunction of Huntingtin
inAxonalTransport ............................................. 115
Fre´de´ricSaudouandSandrineHumbert
ix
x Contents
TheRoleofRetromerinNeurodegenerativeDisease .................. 125
ClaireF.SkinnerandMatthewN.J.Seaman
RegulationofEndocyticTraffickingofReceptorsandTransporters
byUbiquitination:PossibleRoleinNeurodegenerativeDisease ......... 141
AlexanderSorkin
TheSortilin-RelatedReceptorSORL1isFunctionallyandGenetically
AssociatedwithAlzheimer’sDisease ............................... 157
Ekaterina Rogaeva, Yan Meng, Joseph H. Lee, Richard Mayeux,
LindsayA.Farrer,andPeterStGeorge-Hyslop
RegulationofTransportandProcessingofAmyloidPrecursorProtein
bytheSortingReceptorSORLA................................... 167
ThomasE.Willnow,MichaelRohe,andVanessaSchmidt
Index .............................................................181
