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Foguem, Clovis and Kamsu-Foguem, Bernard Neurodegeneration in
tauopathies and synucleinopathies. (2016) Revue Neurologique, vol. 172
(N°11). pp. 709-714. ISSN 0035-3787
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Short
communication
Neurodegeneration
in
tauopathies
and
synucleinopathies
C.
Foguem
a,b,
B.
Kamsu-Foguem
c,*
aEpernayHospitalCentre,137,ruedel’HoˆpitalAuban-Moe¨t,BP137,51205Epernay,France
bCenter for Food and Tastesciences (CSGA), UMR6265 CNRS, UMR 1324 INRA, University ofBurgundy, 9E,
boulevardJeanne-d’Arc,21000Dijon,France
cLaboratoryofProductionEngineering(LGP),EA1905,ENIT-INPTUniversityofToulouse,47,avenued’Azereix,
BP1629,65016Tarbescedex,France
1.
Introduction
Ineveryneurodegenerativedisease,theaccumulationofone or more aggregated proteins has been identified as the molecularsignatureofthedisease[asseenin,forexample, Alzheimer’sdisease(AD),Parkinson’sdisease(PD),dementia withLewybodies(DLB),amyotrophiclateralsclerosis(ALS)
andfrontotemporal dementia(FTD)][1].Theproteinsthat accumulateinthecentralnervoussystemofpatientswith suchdiseaseswereinitiallyidentifiedbythepurificationof polypeptides from the brains of affected humans and animals[2].Itiscurrentlyassumedthatthebasicmechanism ofcelldeathindegenerativediseasesisrelatedtoarather restricted number of processesin which oxidativestress Keywords:
Neurodegenerativediseases Alzheimer’sdisease Parkinson’sdisease DementiawithLewybodies Dementia
a
b
s
t
r
a
c
t
Whileincreasinglifeexpectancyisamajorachievement,theglobalagingofsocietiesraises anumberofmedicalissues,suchasthedevelopmentofage-relateddisorders,including neurodegenerativediseases.Thethreemaindiseasegroupsconstitutingthemajorityof neurodegenerativediseasesaretauopathies,alpha-synucleinopathiesanddiseasesdueto repetitions of glutamine (including Huntington’s disease). In each neurodegenerative disease,theaccumulationofoneormoreaggregatedproteinshasbeenidentifiedasthe molecularsignatureofthedisease(asseen,forexample,inAlzheimer’sdisease,Parkinson’s disease,dementia with Lewybodies,amyotrophic lateral sclerosis andfrontotemporal dementia).The etiology of neurodegenerative diseases is often multifactorial,and the knownriskfactorsinclude,inadditiontogeneticpolymorphismsandage,someother possiblecauses,suchascertainimmuneandmetabolicconditions,endocrinepathologies, gender,socioeconomicorprofessionalstatus,oxidativestressorinflammation,vitamin deficienciesandenvironmentalfactors(chemicalexposure,metals).However,innovative strategiestoelaboratesuitablediagnosticandtherapeuticapproaches(aimingtoatleast delayorpossiblyevenreversediseaseprogression)requirefurtherknowledgeofthegenetic andadaptiveimmunologicalcharacteristicsofneurodegenerativediseases.
*Correspondingauthor.
couldplayacentralrole,resultinginproteindysfunctionand aggregation, which may be signs of differential clinical expressions[3].
Theidentificationofspecificmutationsincertaingenesis oriented towards certain proteins and pathways currently consideredcriticalinthepathogenesisofthemostprominent neurodegenerative diseases (Table 1). These include muta-tionsofprecursorproteins:amyloidbeta(AborAbeta)causes AD; alpha-synuclein leads toPD or DLB; and microtubule-associatedproteintau(MAPT)causesFTDwithparkinsonism. These aberrant misfolded proteins occurred initially in specific brain areas and were secondarily found in wider
areasofthebrainastheneurodegenerativediseasesymptoms worsenedorthediseaseentereditslaterstages(Figs.1and2) [4,5].
Furthermore,theprionconceptexplainshowadiseasecan manifestashereditary,sporadicorinfectious.Inaddition,the common feature of prion diseases (sporadic, dominant inheritance,acquiredthroughinfection)isthattheyinvolve aberrantmetabolismofprionprotein.Animportantfeature thatdistinguishesprionvirusesisthetwoisoformsofprion protein(PrP)encodedbyachromosomalgene.Inhumans,the PrPgeneisdesignatedPRNPandislocatedintheshortarmof chromosome20.
Table1–Intraneuronalfilamentousinclusionsinneurodegenerativediseases.
Disease Filamentousinclusions Maincomponent
Alzheimer’sdisease Neurofibrillarytangles(lesions) Tauprotein Pick’sdisease(typeoffrontotemporal
dementia)
Pickbodies Tauprotein FTDP-17 Neurofibrillarylesions,glialfibrillarylesions Tauprotein Progressivesupranuclearpalsy(PSP) Neurofibrillarylesions,glialfibrillarylesions Tauprotein Corticobasaldegeneration(CBD) Neurofibrillarylesions,glialfibrillarylesions Tauprotein Parkinson’sdisease Lewybodiesandneurites Alpha-synuclein DementiawithLewybodies(DLB) Lewybodiesandneurites Alpha-synuclein Multiplesystematrophy(MSA) Neuronalandglialinclusions Alpha-synuclein
Huntington’sdisease Intranuclearinclusions,dystrophicneurites PolyQrepeatexpansioninhuntingtinprotein Spinocerebellarataxiatype1(SCA1) Intranuclearinclusions PolyQrepeatexpansioninataxiatype1protein Spinocerebellarataxiatype3(SCA3) Intranuclearinclusions PolyQrepeatexpansioninataxiatype3protein Spinocerebellarataxiatype7(SCA7) Intranuclearinclusions PolyQrepeatexpansioninataxiatype7protein DRPLA,orNaito–Oyanagidisease Intranuclearinclusions PolyQrepeatexpansioninataxiatype1protein Spinalandbulbarmuscular
atrophy(SBMA)
Intranuclearinclusions PolyQrepeatexpansioninandrogenreceptor FTDP-17:frontotemporaldementiaandparkinsonismlinkedtochromosome17;PolyQ:polyglutamine;DRPLA:dentatorubral-pallidoluysian atrophy.
Fig.1–Brainanatomicallocationsofprimarymacro-andmicroscopicchanges(misfoldedproteins)arecharacteristicof particularneurodegenerativediseases.PrP:prionprotein;FTD:frontotemporaldementia;AD:Alzheimer’sdisease;LBD: Lewybodydementia(includingParkinsondiseasedementia,PDDanddementiawithLewybodies,DLB);PD:Parkinson’s disease;HD:Huntington’sdisease;ALS:amyotrophiclateralsclerosis.FromBertramandTanzi[4].
2.
Filamentous
inclusions
in
neurodegenerative
diseases
Thethreemain diseasegroupsconstitutingthemajorityof neurodegenerativediseasesarethetauopathies, alpha-synu-cleinopathies and diseases due torepetitions of glutamine (includingHuntington’sdisease;Table1).
Tauopathies(includingAD,FTDandprogressive supranu-clearpalsy)andalpha-synucleinopathies[comprisingmainly PD, DLBand multiplesystematrophy(MSA)] representthe majorityoflate-onsetneurodegenerativediseasesinhumans. Amyloidopathies, tauopathies and synucleinopathies share commonpathologicalfeaturesintermsofstructural, aggre-gatory and spreading properties (the pathophysiological molecularmechanisms leadingtocellular toxicity)[6]. The factorsthatgeneratetauopathyanditsextensionwithinareas ofthebrainarenotwellknown;amyloid precursorprotein (APP)genedysfunctionisthebestcandidatesofar,asrevealed by genetic studies [7]. The development of intracellular
filamentousinclusionscouldbringariskofacuteorchronic toxicity,leadingtoinjuryordamagetobraincells[8].
3.
Etiology
of
neurodegenerative
diseases
Anotherfeatureobservedinthemostcommon neurodege-nerativediseasesisthedichotomybetweenfamilial(rare)and non-familialforms(most common;Table2).Thesearealso frequently described as ‘sporadic’ or ‘idiopathic’, although thereisagrowingbodyofevidencesuggestingthatalarge proportion of these cases are also strongly influenced by geneticfactors.Thegeneticsbehindthesediseaseshasbeen labeled ‘complex’, in contrast to the classical Mendelian geneticsdubbed‘simplex’(singlemodeorsingleinheritance), duetotheinvolvementofnumerousgenesthatarelikelyto have complex interactions with each other and with non-genetic variables as well (Fig. 3). The genetics considered complex would be governed by common deoxyribonucleic Fig.2–Sequentialtopographicaldisseminationofnon-prionproteinsinneurodegenerativediseases.Pathologyisfirst detectedinareasshownindarkercoloursandtheninregionsshowninlightercolours.(aandb)InAlzheimer’sdisease (AD),tauaggregatesdevelopinitiallyinthelocusceruleus(LC),thenintransentorhinalandentorhinalregions,andfinally inthehippocampalformationandwideareasofneocortex(NC).(candd)Incontrasttotaupathology,amyloid-bdeposits inADarefirstseeninNCandtheninallocortical,diencephalicandbasalgangliastructures(caudaldirection),brainstem, andsometimescerebellum(CB).(eandf)Progressionofa-synucleinimmunoreactiveLewybody/neuritepathologyin Parkinson’sdiseasefollowsanascendingpatternfrombrainstemtotelencephalon.Earliestlesionsareintheolfactorybulb (OB)anddorsalmotornucleusofthevagusnerve(DMX)inthemedullaoblongata.(gandh)Inamyotrophiclateralsclerosis withalowburdenofTARDNA-bindingprotein43(TDP43)pathology,TDP43inclusionsareseeninitiallyintheagranular motorcortex(AGN),brainstemmotornucleiofcranialnervesXII–X,VIIandV,anda-motorneuronsinthespinalcord.AC: allocortex;BFB:basalforebrain;BN:brainstemnuclei;BSM:brainstemsomatomotornuclei;ENT:entorhinalcortex;MTC: mesiotemporalcortex;PFN:prefrontalneocortex;SC9:spinalcordgray-matterlaminaIX;SN:substantianigra;TH: thalamus.ReprintedfromBrettschneideretal.[5]andBraaketal.[16].acid(DNA)variants,suchassinglenucleotidepolymorphisms, which significantly increase the risk of disease, yet are insufficienttoeffectivelycauseadisorderorspecificdisease. Innovative strategies to elaborate suitable therapeutic approaches(aimingtoatleastdelayandpossiblyevenreverse disease progression) require knowledge of the genetic and adaptiveimmunologicalcharacteristicsofthese neurodegene-rativediseases.Geneticevidencesupportstheideathatmultiple neurodegenerativepathwaysleadtomildcognitiveimpairment andthattheeventualconversiontodementia,principallyof theADsubtype,isessentiallyduetotheADpathway(s)[9].
The etiology of neurodegenerative diseases is often multifactorial, although these chronic diseases share two maincharacteristics:
neuronal loss in motor, sensory or cognitive systems, generatingmentalandmotordecline;
a strong association between metabolic changes and neurodegeneration (for example, disruption of the link betweentheperipheral organsgoverning energy metabo-lismandthecognitiveandneuralsystems)[10].
The known risk factors for neurodegenerative diseases include,inadditiontogeneticpolymorphismsandage,other
possiblecausessuchascertainendocrinepathologies,gender, socioeconomic or professional status, oxidative stress or inflammation,vitamindeficiencies[especiallyofvitaminB9 (folicacid)andvitaminB12],immuneandmetabolic condi-tions,andenvironmentalfactors(suchaschemicalexposure andheavymetals;Fig.3).Indeed,somestudieshaverevealed correlationsbetweenchronicpesticideexposuresin occupa-tionalsettingsandthedevelopmentofneurologicaldisorders [11].Inaddition,epigeneticregulationofgeneexpressionand environmentalmodulationarefactorsthatmayplayakeyrole intheonsetandcourseofcommonneurologicalconditions, including AD, PD, Huntington’s disease (HD) and multiple sclerosis(MS)[12].Theimmunesystemalsohasanimportant roleinneurodegenerativedisorders:whilethereare undoubt-edly maladaptivecomponents ofneural inflammation that servetospreadaneurotoxicenvironmentthatcanencourage neuropathogeniclesions,thereisalsotheopportunitytouse adaptive and beneficial microglial/monocyte phenotypes to enablebeneficialneuroimmuneresponsesinsome neurode-generativediseases(suchasADandPD)[13].
4.
Discussion
The degenerative processes in brain cells are considered ‘primary’ when no causal factor can be identified, and ‘secondary’whentriggeringfactorsaredemonstrated (inflam-matoryfactors,ortoxic,metabolicortraumaticevents).These triggeringfactors ofneurodegenerativepathologiesarestill mostly unknown, making a timely and accurate diagnosis difficulttoachieveduringantemortemassessmentofthese diseases[1].Althoughincertaincases,thediagnosismadebya clinician can be confirmed postmortem by pathological examination,it isgenerally acceptedthatdiagnostic errors maybeidentifiedfromthepatient’spostmortemanatomical pathologicalfindings.Inmanysituations,therearedifficulties indiagnosis,assomeneurodegenerativediseaseshavemany signs and symptoms in common. The diagnosis of DLB is particularlydifficultassomeofitssymptomscanbefoundin otherneurodegenerativediseases,suchasPDandAD,thereby oftenleadingtoitsmisdiagnosis.
COMM
ON NEUR
ODE
GENER
ATIVE
DISEASES
IN THE
ELDER
LY: KE
Y POI
NTS
Synuclein, Tau and Glutamine Dysfunctions
Synuclein, Tau and Glutamine Aggregations
Neurodegenerative Diseases
?
Genetic
Factors
Alpha -Synuclein Mutations Tau Mutations
Repetitions of glutamine
Non-Genetic
Factors
Professional socio-economic or professional status Individual variables (gender and age)
Environmental Factors (chemical exposure, metals, etc.)
Inflammation, vitamin deficiencies, immune and metabolic conditions
Fig.3–Spectrumofriskpredisposingtocommonneurodegenerativediseases.Thisregroupingdistinguishesgenetic predispositionfromnon-geneticfactors.
Table2–Etiologicalfrequency(sporadic,geneticand
infectious)ofneurodegenerativepathologies.
Diseases Etiologicalfrequency(%) Sporadic Genetic Infectious
Priondisease 85 >10 <1 Alzheimer’sdisease 90 10 Parkinson’sdisease 95 <5 Frontotemporaldementia 90 10 Pick’sdisease 95 <5 Progressivesupranuclear palsy(PSP) 95 <5 Amyotrophiclateral sclerosis(ALS) 90 10 Huntington’sdisease(HD) 100 Spinocerebellarataxia(SCA) 100
AD is the most common neurodegenerative disease, affecting20to25millionpeopleworldwide,andisthefourth leading cause of death in industrialized countries. Its prevalence rate is around 7%in those aged65,with the doublingofriskforevery5yearsafterage65.Somestudiesof ADsuggestthatthegeneencodingspondin1(SPON1)maybe associatedwiththedifferentialrateofcognitivedeclineinAD patients[14,15].
PDisthesecondmostcommonneurodegenerativedisease associatedwithintraneuronal filamentousinclusionsmade up of aggregated alpha-synuclein in Lewy bodies and dystrophicneurites.Itaffectsbetweensixandsevenmillion peoplearoundtheworld.SomerarefamilialformsofPDare causedbymutationsofthegeneforalpha-synuclein[8].
DLB is the second most common neurodegenerative dementiaafterAD,andthesecondmostcommon synuclei-nopathy after PD, FTD represents 5–10% of all dementias, including Pick’s disease. These disorders are related to mutationsofthetaugeneinfamilialFTDandparkinsonism linked to chromosome 17 (FTDP-17). For most of these diseases, the definitive diagnosis can only be made by pathologicalexaminationofbraintissue.
The primary neurodegenerative diseases that lead to a dementiasyndromehaveanumberofcommon characteris-ticsandconstituteaconsistentsetoffeatures:
theneurodegenerativeprocessisslowandcantake20years beforetheonsetofitsfirstclinicalmanifestations,makingit difficulttoprecisely date the beginningofthe diseaseor eventhestartofthefirstclinicalsigns;
thebraindamageisirreversible,sotheclinicalsignspersist overtime;
thesymptomatologyandallclinicalsignsofthedementia areimportant;
thecourseoftheillnesstrendstowardsalossof indepen-dence.
5.
Conclusion
Thereisaccumulatingevidencethatmostneurodegenerative diseases are due to deposits of aberrantly misfolded and aggregatedbrainproteins.Pathologieswithaprimary degene-rativeprocessmainlyincludeAD,PD,DLB,ALS,HD,FTDand priondiseases.ADischaracterizedbydegenerationofneuronal cellsduetofilamentousneuronalinclusions,comprisingthe microtubule-associatedproteintauinahyperphosphorylated state;tauisthekeyconstituentofneurofibrillarytanglesand hasasynergisticrelationshipwithAPPdysfunction.
The pathological accumulation of alpha-synuclein and Lewy bodiesinthe brainsofPD patients(aspostulatedby Braaketal.)[16]couldleadtothedevelopmentofapredictable six-stagesequenceoflesions,basedonastepwise patholo-gical progression starting from the medullary nuclei and olfactorycortex.Implementationofsuchastagingstrategyto categorizethedegreeofpathologyinPDmighttheninfluence the patient’s final diagnosis [16,17]. However, it has been shown that, incertain rare cases, there is no relationship betweentheBraakstageandclinicalseverityofPD[18].
TheclinicalsyndromeofDLBseemstobedirectlyrelatedto Lewy body pathology and is often inversely related tothe pathologicallesionsassociatedwithAD.Thus,DLB neuropa-thological criteria could be useful for making a precise diagnosis.In particular,avisual semi-quantitative analysis couldbeusedtodifferentiateDLBfromPDinthebrain:lesions in the latter have a distribution predominantly in the brainstem whereas, in the former, the distribution and frequencyofLewy bodiesarelikelybediffusedthroughout the neocortex. Imaging of the dopaminergic system using
123
I-fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl)-nortropane(FP-CIT)single-photonemissioncomputed tomo-graphy (SPECT) may represent an accurate method for differentiatingDLBfromotherdementiasyndromes[19].
Filamentousinclusionsoftauproteinhavebeenidentified in the brains of patients with FTD, and especially Pick’s disease.Thishasbeenrevealedtobeduetomutationsinthe taugeneinfamilialformsofFTD,thusprovidingadirectlink betweentauproteindysfunctionanddementiaseverity[8].
Finally, inMSA, which isless common thantheother neurodegenerativepathologiesandoftenconfusedwithPD attheclinical level,theaccumulationofmisfolded alpha-synucleinhasbeendescribed,aswellasmultipleformsof neuraldegenerationsimilartothosefoundinPDandDLB [20].
Infuture,thedevelopmentofstrategiestoelaboratenew potentially therapeutic approaches and offurtherresearch aimedatthediscoveryofnoveldrugsforneurodegenerative diseases will require greater knowledge of the innate and adaptiveimmunologicalaspectsofneurodegenerative disea-ses(suchasthosefoundinPD,ADandALS)[21,22].
Ethical
approval
Theauthorsagreewithethicalapprovalandinformedwritten consent.
Disclosure
of
interest
Theauthorsdeclarethattheyhavenocompetinginterest.
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