Jee Eun Yang, Seung R. Paik · 2013-05-30 · HMR Jee Eun Yang, et al. • Amyloidogenic Protein of α-Synuclein Hanyang Med Rev 2013;33:123-129 질들이 선택적 상호결합에

© 2013 Hanyang University College of Medicine 123http://www.e-hmr.org

Amyloidogenic Protein of α-Synuclein Jee Eun Yang, Seung R. Paik

School of Chemical and Biological Engineering, Seoul National University, Seoul, Korea

서 론

파킨슨병(Parkinson’sdisease,PD),알츠하이머병(Alzheimer’sdisease,AD),전염성해면양뇌증(transmissiblespongiformen-cephalopathy,TSE)등을포함하는대부분의퇴행성신경질환들

에서는세포안팎에비정상적단백질축적에의한아밀로이드성단백질섬유의침착이확인된다.아직까지이와같은병리현상과세포

퇴화의상관관계에대해서는명확히밝혀진바없으나산화적스트레스,세포내단백질가수분해억제에따른비정상적단백질의축적,세포내소기관인미토콘드리아나리소좀등의파괴등이세

Hanyang Med Rev 2013;33:123-129http://dx.doi.org/10.7599/hmr.2013.33.2.123

pISSN 1738-429X eISSN 2234-4446

Amyloidogenesis is the key pathological phenomenon commonly observed in various neurodegenerative disorders. α-Synuclein is the major constituent of Lewy bodies as a common pathological signature of Lewy body diseases (LBDs) including Parkinson’s dis-ease (PD), PD with dementia (PDD), and Dementia with Lewy bodies (DLB). As proteins unfold, they would result in producing either ordered or disordered aggregates unless they are folded back to the native state by molecular chaperones or removed via proteo-lytic degradation. α-Synuclein known as a natively unfolded protein has self-assembled into the ordered protein aggregates of amyloid fibrils which comprise the radiating fila-ments found in Lewy bodies. Amyloid fibrils are generated via either a template-depen-dent or template-independent mechanism. The prevalent nucleation-dependent fibrilla-tion accelerates the assembly process in the presence of seeds such as prefibrillar species. As a template-independent process, we have recently proposed the double-concerted fi-brillation mechanism in which the oligomeric species of α-synuclein act as a growing unit to form the mature fibrils. Despite insufficient understanding of the toxic causes of α-synu-clein, the oligomeric species have been suggested to be responsible for the cellular de-generation by influencing membrane stability while leaving the amyloid fibrils as a detoxi-fication end product. Alternatively, the transition process from the oligomers to the fibrils has been proposed to affect cell viability. It is, therefore, expected to develop prophylactic and therapeutic strategies toward the synucleinopathies by studying cellular function of α-synuclein, molecular mechanism of its assembly into the amyloid fibrils, and their effects on cellular biogenesis. By studying cellular function of α-synuclein, its molecular mecha-nism of assembly into amyloid fibrils and their effects on cellular biogenesis, progress of prophylactic and therapeutic strategies toward synucleinopathy can be seen.

Key Words: Amyloidosis; Neurodegenerative Disorders; Parkinson Disease; alpha-Synu-clein

아밀로이드성 단백질 α-Synuclein

양지은·백승렬

서울대학교 공과대학 화학생물공학부

Correspondence to: Seung R. Paik우151-744, 서울시 관악구 관악로 1,서울대학교 제2공학관 302동 911호School of Chemical and Biological Engineering, Seoul National University, 302-911, 1 Gwanak-ro, Gwanak-gu, Seoul 151-744, Korea Tel: +82-2-880-7414 Fax: +82-2-888-7295E-mail: [email protected]

Received 10 March 2013Revised 29 April 2013 Accepted 3 May 2013

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom-mons.org/licenses/by-nc/3.0) which permits un-restricted non-commercial use, distribution, and reproduction in any medium, provided the origi-nal work is properly cited.

124 http://www.e-hmr.org

Jee Eun Yang, et al. • Amyloidogenic Protein of α-SynucleinHMR

Hanyang Med Rev 2013;33:123-129

포사멸의원인후보로알려진다.노화관련질환으로지속형이며동시에비가역적인퇴행성신경질환들의치료책으로는퇴화된신경세포로부터분비되어야할신경전달물질을외부로부터제공하

거나세포이식및외과적수술등이수행되고있으나여전히많은위험요소가상존하고있는상황이다.따라서,퇴행성신경질환의원인으로의심되고있는아밀로이드형성기전과관련된세포퇴화

의분자기전을이해함으로써보다효과적인퇴행성질환의예방및치료책개발이가능하게될것으로기대한다.

본 론

1 아밀로이드와 퇴행성신경질환

1) 단백질 응집현상

단백질응집현상은단백질잘못된접기(proteinmisfolding)와단백질의비정상적축적현상에의해나타나며정형과비정형응집

물로구분할수있다.퇴행성신경질환등에서관찰되는아밀로이

드는정형응집물의예이며대장균내에서단백질을과발현하였을경우확인되는내포체(inclusionbody)는비정형응집물의예로이해할수있다[1-3].단백질응집은일반적으로단백질의접기(folding)와풀어짐(un-

folding)과정에확인되는부분적으로접기중간체(partiallyfoldedintermediate)로부터유도된다(Fig.1).정상적생리조건에서는구조적불안정성을나타내는단백질의중간체들은분자샤페론이나프로테아좀(26Sproteasomesystem)에의해원래상태의접기구조로되돌아가거나아미노산으로분해되어세포로부터제거되어

야한다.만일그렇지않을경우,이들접기중간체들은세포내에축적되어자가조립화과정을거쳐단백질응집물로발전하게되며세포독성의원인물질로작용하는것으로알려진다.접기중간체내에는분자내상호작용을나타내는핵심영역을

기준으로소수의단백질2차구조와완전히풀어헤쳐진영역을함께갖고있다.단백질의자연구조와유사한상태를유지하고있는

중간체의경우이들잔존하는영역간상호작용,즉,기하학적상보

성,폴리펩티드의골격상특징,다양한비공유성상호작용등에의해원래상태의구조로되돌아갈수있다.그러나구조적변형이다소지나치게되어단백질의소수성영역이노출되게될경우,이들소수성-소수성상호작용이분자간조립화의주된인력으로작용

하여단백질응집으로이어지게된다.실질적으로소수성영역이단백질전체영역에퍼져있게되는완전히풀어헤쳐진단백질보다소수성영역이부분적으로클러스터를형성하는접기중간체의경우단백질응집유도에더효과적인것으로알려진다.따라서,이와같은단백질의접기중간체를유도하고안정화시킬수있는인자

들,예를들어단백질(중간체)농도,아미노산서열,pH및이온세기

와같은용액조건,단백질리간드를비롯한단백질상호작용성물질등은단백질응집에많은영향을미칠수있다.

2) 아밀로이드

아밀로이드란물에잘녹는단백질이여러생물및화학적조건

에서단백질간선택적이며특이적상호작용에의해비수용성의섬유상구조물로전환된결과물로정의한다[1].아밀로이드는위에서제시한다양한퇴행성신경질환에서공통으로관찰되는단백질응집물[4,5]로서신경세포퇴화의주된원인물질로알려지고있다.일반적으로아밀로이드는격자모양의beta-sheet구조를나타냄으

로써[6]단백질골격간수소결합과섬유체구성단백질들이서로직각으로위치하며,따라서거미줄과비교될정도의높은강도를나타낸다[7].이렇게형성된섬유상구조물은폭10-20nm가량의단백질나노섬유를형성하며미래나노-바이오테크놀러지분야의주요소재로사용될것으로기대된다(Fig.2).이런아밀로이드에의한세포퇴화유도기전은아직까지명확히

밝혀지지않고있음에도불구하고,아밀로이드와관련된소수의

Fig. 1. Intracellular folding of proteins and formation of protein ag-gregations (Ref. 3 with permission from Biochemistry and Molecular Biology News).

Ordered aggregates (Amyloid fibrils)

Proteasomal degradation

Folded Partially-folded intermediate

Molecular chaperone Amorphous aggregates

(Inclusion bodies)

Unfolded

Fig. 2. Amyloid structure of PD-related α-synuclein (Ref. 3 with per-mission from Biochemistry and Molecular Biology News).

Amyloid fibrils

115 Å24 β-strands

~10 nm

http://www.e-hmr.org 125

양지은 등 • 아밀로이드성 단백질 α-Synuclein HMR


세포독성모델들이제안되고있다.1)아밀로이드에의한세포외조직으로의물리적침입과그에기인하는정상조직의형태및기능의파괴[8,9];2)아밀로이드생성과정의중간산물인올리고머-중간체

(oligomericintermediate)에의한세포막또는세포내미토콘드리

아내막등의지질막구조의불안정화(최종산물인아밀로이드는독성중간체를제거한단순한해독산물이라는모델)[10,11];3)산화-환원성전이금속(철,구리)등의아밀로이드흡착과그에따른활성산소의생성에의한세포사멸유발[12,13];4)단백질응집물에의한세포의일반적생리활성인자의선택적제거따른세포퇴화등이제안된다.따라서,아밀로이드형성원리를분자수준에서이해하

고이를제어하는방법을개발하는것은세포퇴화의분자원인을제어한다는의미에서상기퇴행성신경질환을근본적으로대처하

는예방및치료책개발의좋은밑거름이될것으로여겨진다.아밀로이드가퇴행성신경질환에서공통으로관찰되는구조체

이기는하지만그형태를세밀히분석해보면섬유상구조의형태

학적다형성(fibrillarpolymorphism)이확인된다.심지어한종류

의단백질도아밀로이드가형성되는조건에따라다양한형태의아밀로이드로전환됨을확인할수있다[14].이를설명하기위해서아밀로이드형성기전을형틀-의존성(template-dependent)기전과형틀-비의존성(template-independent)기전으로구분하여이해할필요가있다.형틀-의존성아밀로이드형성기전은이미생성된형틀에아밀로이드성단백질이구조적변형을나타내면서순차적으

로결합함으로써단백질섬유가성장하는과정이다.이때작동할수있는형틀로는변형된구조의단백질단량체,올리고머-중간체,미성숙단백질섬유및아밀로이드단편등이형틀로서의기능을수행할수있다(Fig.3).반면형틀에결합하게될단백질은단일단백

질임에도불구하고구조적엔트로피가높은상태에있음으로써다양한구조가화학적평형상태에놓여있게된다.이런구조중특정구조가특정형틀에의해아밀로이드로제거되게되면단백질의구조간평형은제거된구조쪽으로이동하게됨으로써초기형틀

의구조에의존적인특정형태의아밀로이드가최종산물로생성되

게된다.즉,아밀로이드형성은일종의단백질의무질서-질서전이현상(disorder-to-ordertransition)의산물이라고할수있다.반면,형틀-비의존성기전은구조적평형상태에있는아밀로이드성단일

단백질이특정리간드와결합함으로써자기조립성활성이높은구조로전환되고그에따라아밀로이드가형성되는기전으로리간드

의종류에따른다양화된아밀로이드가유도되는특성을나타낸

다(Fig.4).아밀로이드형성과정을단백질응집동력학으로분석하게되면

크게세단계-지연기(lagphase),대수-생장기(exponentialgrowthphase),정지기(stationaryphase)로구분할수있다[15].이과정을설명하는가장인지도가높은모델은핵-의존성응집기전(nucle-ation-dependentfibrillation)이다(Fig.5).초기응집핵의형성은상기형틀-비의존성과정을통해이루어짐으로써특정구조의단백

Fig. 3. Template-dependent fibrillation. (A) Fibrillar growth with active monomers. The monomers convert to the amyloidogenic conformer upon binding to the template. (B) Amyloid fibril growth with passive monomers. The amyloidogenic conformers are selected by the template from the pre-existing conformational equilibrium and amyloid fibrils are elongated. (Ref. 14 with permission from BMB Reports).

Natively or partially unfolded protein

Template Protein binding to the template

Induced-fit type structural adjustment

A

Template

Various conformers

Selection

Depletion of 'circular' form

Binding of 'circular' form

Amyloid fibrillar growth

Shift in equilibrium Shift in equilibrium

B




질들이선택적상호결합에의해유도될것으로예상된다.이과정

은열역학적으로다소불리한프로세스로지연기(lagphase)에서확인되는바와같이시간적지연효과가관찰된다.그러나일단응집핵이형성되게되면형틀-의존성기전에의해가속화된아밀로

이드의생성이유도되며응집동력학상에서는대수-생장기(expo-nentialphase)로관찰되게된다[16-18].일정기간동안의아밀로이

드성장이지속된후,응집동력학은정지기(stationaryphase)에접어들게되는데응집에필요한단백질농도가충분히확보되지않았거나아밀로이드와용액상단백질간평형등의원인에기인할것으로추정된다.최근들어본연구진은상기삼단-응집동력학을이중협동성응

집기전(double-concertedfibrillation)으로새롭게설명하였다(Fig.5).즉,응집과정의초기단계에단백질단량체로부터형성된올리고

머가응집단위로작용하여두번째단계인단위조립화과정을통해아밀로이드로성장하는현상으로핵-비의존성기전의한예를실험적으로증명하였다.이를통하여아밀로이드의생성과정의다양한분자기전이아밀로이드의다형성의원인으로판단되며,나아

가아밀로이드에의한세포지질막구조물의불안정화측면에서세포독성의차별성을초래하는원인이될가능성을제안하고있다.

2. 파킨슨병 관련 단백질 α-Synuclein

1) 파킨슨병 (Parkinson’s disease, PD)

파킨슨병(PD)은퇴행성신경질환중노인성치매에이어두번째

로흔한노화관련질환으로65세이상노인의2%가량이이병으

로고통받고있으며,미국에서만약백만명의환자가있다.이병은손떨림,강직증세,느린운동성,자세의불안정성등과같은운동기

능의장애가나타나며,정서불안및공포감등의정서적장애가동반된다.병의전개과정이점진적이며,병리학적으로뇌의흑질내도파민성신경세포의심각한퇴화(약70-80%)가관찰된다.이들세

Fig. 4. Template-independent fibrillations. (A) Ligand-induced fibrillation, (B) Fibrillar polymorphisms induced by multiple ligand interactions (Ref. 14 with permission from BMB Reports).

Amyloidogenic conformer

Ligand

Amyloid

A

Amyloidogenic conformer A

Ligand 1

Type AAmyloid

Type BAmyloid

Ligand 2

Amyloidogenic conformer B

B

Fig. 5. Models of amyloidogenesis. (A) Nucleationdependent fibrilla-tion, (B) Double- concerted fibrillation (Ref. 14 with permission from BMB Reports).

Oligomer Monomer

Monomers Nucleus Monomers accretion Amyloid

A

Monomers Granule Conformational distortion

Physical or chemical influences

Granular assembly Amyloid

B




포내에서는루이소체(Lewybody)라고하는단백질의비정상적침착이확인된다[1].

PD발병의유전적요인으로는파킨슨병가계에서관찰되는돌연변이성유전자로서α-synuclein,parkin,그리고ubiquitinC-ter-minalhydrolaseL1(UCHL1)등세가지가대표적이다.우성형질PD는α-synuclein유전자의변이발생이원인이며,열성형질PD는parkin유전자의변이가원인인것으로알려진다[19].사실상이와같은유전적요인에의한PD의발병은전체의극히일부에해당하

며,PD의발병요인중대부분은아직까지정확히밝혀지지않은환경적요소가주요요인으로알려진다.현재까지보고된바에따르

면PD에서확인되는뇌흑질내도파민성신경세포의퇴화는세포내단백질응집현상과밀접한관계가있음이확인되고있다.예를들어산발성PD의경우,루이소체의주성분으로α-synuclein축적

이보고되었으며,도파민성신경세포의퇴화에중요한역할을할것으로추정된다.

2) α-Synuclein

PD를비롯한루이소체질환(Lewybodydiseases,LBDs)은시냅

스전단백질인α-synuclein의비정상적인축적으로인한루이소체형성이대표적병리현상으로알려지며synucleinopathies라고도불린다[4,5].따라서,α-synuclein의응집과정과병리학적기능등의이해는상기질환의진단,예방및치료책을확보하는데중요할것으로판단된다.

α-synuclein은140개아미노산으로이루어져있으며pKa값이4.7에해당하는산성단백질[20]로서자연상태에서비정형구조로존재하는것으로알려진다[21].α-synuclein은1차구조상N-말단

의amphipathicα-helical영역,C-말단의산성영역,그리고가운데

의소수성non-amyloidcomponent(NAC)영역으로나뉜다(Fig.6).염기성아미노산인리신(lysine)이풍부한N-말단은세포막과liposome등과상호작용을하여단백질의자가중합체를유도하고calmodulin과synphilin-1등과도상호작용하는것으로알려져있다.C-말단은α-synuclein의핵에서의위치를조절하고구리,철,칼슘등의금속과결합하며단백질중합체를유도하는것으로알려

져있다[20-22].아미노산서열65-90번에해당하는NAC영역은α-synuclein의응집에필수적인부분으로이영역이일부제거되는경우α-synuclein올리고머형성이나섬유화현상이현저히감소함

을확인할수있다[23,24].현재까지α-synuclein은신경세포사이의신경전달물질방출과

시냅스형성의가소성을조절하는생리적기능을하는것으로보고되고있다.실제로α-synuclein은시냅스전말단에서주로관찰

되고있으며[25,26],Snca-knockoutmice와humanα-synucleintransgenicmice에서α-synuclein의신경세포내발현정도에따라시냅스전달에결함이관찰된다[27-31].또한,최근보고에따르면α-synuclein은시냅스전solubleNSFattachmentproteinreceptor(SNARE)복합체의조립을조절함으로써샤페론단백질로서의역할을수행하는것으로알려져있다[32].루이소체질환에서발견되는세포내α-synuclein의비정상적축

적물과재분배는병리현상과밀접한관계가있는것으로알려져있으며실제로α-synuclein의유전자도입동물실험에서확인되고있다[33].중추신경계내α-synuclein의양은단백질가수분해효소

[34],분자샤페론[35],자가소화작용[36]등으로제어되고이에관여하는분자들의양적변화와SNCA유전자의증식및돌연변이체발생[37]으로α-synuclein의축적이촉진되는것으로보고된다.

α-synuclein은올리고머,미성숙섬유체,섬유체등여러형태로존재하고질환의발병원인이되고있으며특히섬유상구조물이신경세포내루이소체에서주로발견된다[38].이러한아밀로이드성단백질섬유체는열역학적으로안정한구조이며독성을갖는올리

고머가아밀로이드구조로변환되는과정은독성을감소시키려는노력의산물로생각된다.반면올리고머들은세포막투과성에영향

을주어비정상적인칼슘유입과함께세포사멸을나타낸다[39].이들올리고머는생체내병태생리학적조건에따라구형,쇄상,고리모양등다양한형태로존재하며최종섬유체형성이전단계에서관찰되고있다[40].또한α-synuclein은지질및작은분자들과의상호작용,산화적스트레스,단백질합성후변형[41,42]등과같은생리및병리학적요인에의해독성올리고머형성이촉진된다.이와함께단백의농도증가와배양시간,그리고금속의첨가[41,43]리간드상호작용[44]등에의해다양한크기의응집체들이유도된다.이외에도α-synuclein이세포독성을나타내는가능성으로는올리

고머형성에따른세포내기능성단량체의양적공간적,그리고구조적변화로인해α-synuclein의생리학적기능이손실되거나비정

상적세포막및단백질상호작용을통해세포의정상기능을방해

함으로써응집현상과는무관하게독성을나타낼것이라는것이다

[45,46].그러나현재까지서로다른단량체를구별할수있는실험방법적한계가있어α-synuclein단량체가질병에미치는영향에대한연구는여전히도전대상이되고있다.

결 론

아밀로이드형성은다양한퇴행성신경질환에서공통적으로관Fig. 6. Primary structure of α-Synuclein and its interactive ligands. NAC, non-amyloid component.

Amphipathic α-helices

· Liposome· Calmodulin· Synphilin-1

· Aβ25-35· Eosin· CBB-G/R

· Metals (copper, zinc, calcium)· Polycations

1 61 95 140

Acidic regionNAC




찰되는병리학적현상이다.PD를비롯한PD성치매및루이소체

성치매를포함하는루이소체질환에서관찰되는루이소체는α-synuclein을주성분으로한다.접히지않은α-synuclein단백질은분자샤페론에의해원형으로접히지않거나단백질가수분해에의해제거되지않으면정형의혹은비정형의응집체를형성하게된다.자연상태에서접히지않는형태인α-synuclein은자가조립을통해정형단백질응집물인아밀로이드섬유체를형성하며이는루이

소체에서발견되는방사형섬유상을포함한다.아밀로이드섬유는형틀-의존성혹은형틀-비의존성기전을통해형성된다.일반적으로이해되고있는핵-의존성섬유형성은미성숙섬유체와같은seed가존재할때조립과정이촉진된다.우리는형틀-의존성과정에따라α-synuclein의올리고머가응집단위로작용하여완전한섬유체로성장한다는이중협동성응집기전을제안해왔다.α-synuclein의독성원인에대해서는정확히알려진바없지만올리고머가세포막안정성에영향을줌으로써세포파괴에중요한역할을할것으로추정하고있으며,혹은올리고머가응집되는과정에서세포의생존에영향을줄것으로보인다.따라서,α-synuclein의세포기능,아밀로

이드형성분자기전그리고세포내합성에미치는영향에대해연구함으로써synucleinopathies에대한예방및치료책을개발할것으로예상된다.

REFERENCES

1. SipeJD.Amyloidosis.AnnuRevBiochem1992;61:947-75.2. VirchowR.Zurcellulose-frage.VirchowsArchiv1855;8:140-4.3. LeeJH,PaikSR.Strategytocontroltheproteinaggregation:neurodegen-

erativedisordersandamyloid.KSBMBNews2006;27:23-9.4. BraakH,BraakE.PathoanatomyofParkinson’sdisease. JNeurol

2000;247Suppl2:II3-10.5. ShultsCW.Lewybodies.ProcNatlAcadSciUSA2006;103:1661-8.6. SundeM,BlakeCC.Fromtheglobulartothefibrousstate:proteinstruc-

tureandstructuralconversioninamyloidformation.QRevBiophys1998;31:1-39.

7. KnowlesTP,FitzpatrickAW,MeehanS,MottHR,VendruscoloM,Dob-sonCM,etal.Roleofintermolecularforcesindefiningmaterialproper-tiesofproteinnanofibrils.Science2007;318:1900-3.

8. TanSY,PepysMB.Amyloidosis.Histopathology1994;25:403-14.9. MerliniG,BellottiV.Molecularmechanismsofamyloidosis.NEnglJ

Med2003;349:583-96.10. LashuelHA,HartleyD,PetreBM,WalzT,LansburyPTJr.Neurodegen-

erativedisease:amyloidporesfrompathogenicmutations.Nature2002;418:291.

11. CaugheyB,LansburyPT.Protofibrils,pores,fibrils,andneurodegenera-tion:separatingtheresponsibleproteinaggregatesfromtheinnocentby-standers.AnnuRevNeurosci2003;26:267-98.

12. CuajungcoMP,GoldsteinLE,NunomuraA,SmithMA,LimJT,AtwoodCS,etal.Evidencethatthebeta-amyloidplaquesofAlzheimer’sdiseaserepresenttheredox-silencingandentombmentofabetabyzinc.JBiolChem2000;275:19439-42.

13. OpazoC,HuangX,ChernyRA,MoirRD,RoherAE,WhiteAR,etal.

Metalloenzyme-likeactivityofAlzheimer’sdiseasebeta-amyloid.Cu-de-pendentcatalyticconversionofdopamine,cholesterol,andbiologicalre-ducingagentstoneurotoxicH(2)O(2).JBiolChem2002;277:40302-8.

14. BhakG,ChoeYJ,PaikSR.Mechanismofamyloidogenesis:nucleation-dependentfibrillationversusdouble-concertedfibrillation.BMBRep2009;42:541-51.

15. NaikiH,GejyoF.Kineticanalysisofamyloidfibrilformation.MethodsEnzymol1999;309:305-18.

16. JarrettJT,LansburyPT,Jr.Seeding“one-dimensionalcrystallization”ofamyloid:apathogenicmechanisminAlzheimer’sdiseaseandscrapie?Cell1993;73:1055-8.

17. HarperJD,LansburyPT,Jr.ModelsofamyloidseedinginAlzheimer’sdiseaseandscrapie:mechanistictruthsandphysiologicalconsequencesofthetime-dependentsolubilityofamyloidproteins.AnnuRevBiochem1997;66:385-407.

18. WoodSJ,WypychJ,SteavensonS,LouisJC,CitronM,BiereAL.alpha-synucleinfibrillogenesisisnucleation-dependent.ImplicationsforthepathogenesisofParkinson’sdisease.JBiolChem1999;274:19509-12.

19. PolymeropoulosMH,LavedanC,LeroyE,IdeSE,DehejiaA,DutraA,etal.Mutationinthealpha-synucleingeneidentifiedinfamilieswithPar-kinson’sdisease.Science1997;276:2045-7.

20. UlmerTS,BaxA,ColeNB,NussbaumRL.Structureanddynamicsofmicelle-boundhumanalpha-synuclein.JBiolChem2005;280:9595-603.

21. EliezerD,KutluayE,BussellR,Jr.,BrowneG.Conformationalpropertiesofalpha-synucleininitsfreeandlipid-associatedstates.JMolBiol2001;307:1061-73.

22. RecchiaA,DebettoP,NegroA,GuidolinD,SkaperSD,GiustiP.Alpha-synucleinandParkinson’sdisease.FASEBJ2004;18:617-26.

23. GiassonBI,MurrayIV,TrojanowskiJQ,LeeVM.Ahydrophobicstretchof12aminoacidresiduesinthemiddleofalpha-synucleinisessentialforfilamentassembly.JBiolChem2001;276:2380-6.

24. IwaiA,MasliahE,YoshimotoM,GeN,FlanaganL,deSilvaHA,etal.Theprecursorproteinofnon-AbetacomponentofAlzheimer’sdiseaseamyloidisapresynapticproteinofthecentralnervoussystem.Neuron1995;14:467-75.

25. WithersGS,GeorgeJM,BankerGA,ClaytonDF.Delayedlocalizationofsynelfin(synuclein,NACP)topresynapticterminalsinculturedrathip-pocampalneurons.BrainResDevBrainRes1997;99:87-94.

26. JakesR,SpillantiniMG,GoedertM.Identificationoftwodistinctsynu-cleinsfromhumanbrain.FEBSLett1994;345:27-32.

27. CabinDE,ShimazuK,MurphyD,ColeNB,GottschalkW,McIlwainKL,etal.Synapticvesicledepletioncorrelateswithattenuatedsynapticrespon-sestoprolongedrepetitivestimulationinmicelackingalpha-synuclein.JNeurosci2002;22:8797-807.

28. AbeliovichA,SchmitzY,FarinasI,Choi-LundbergD,HoWH,CastilloPE,etal.Micelackingalpha-synucleindisplayfunctionaldeficitsinthenigrostriataldopaminesystem.Neuron2000;25:239-52.

29. ScottDA,TabareanI,TangY,CartierA,MasliahE,RoyS.Apathologiccascadeleadingtosynapticdysfunctioninalpha-synuclein-inducedneu-rodegeneration.JNeurosci2010;30:8083-95.

30. NemaniVM,LuW,BergeV,NakamuraK,OnoaB,LeeMK,etal.Incre-asedexpressionofalpha-synucleinreducesneurotransmitterreleasebyinhibitingsynapticvesiclereclusteringafterendocytosis.Neuron2010;65:66-79.

31. LundbladM,DecressacM,MattssonB,BjorklundA.Impairedneuro-transmissioncausedbyoverexpressionofalpha-synucleininnigraldo-pamineneurons.ProcNatlAcadSciUSA2012;109:3213-9.

32. BurreJ,SharmaM,TsetsenisT,BuchmanV,EthertonMR,SudhofTC.Alpha-synucleinpromotesSNARE-complexassemblyinvivoandinvi-




tro.Science2010;329:1663-7.33. VekrellisK,XilouriM,EmmanouilidouE,RideoutHJ,StefanisL.Patho-

logicalrolesofalpha-synucleininneurologicaldisorders.LancetNeurol2011;10:1015-25.

34. IwataA,MaruyamaM,AkagiT,HashikawaT,KanazawaI,TsujiS,etal.Alpha-synucleindegradationbyserineproteaseneurosin:implicationforpathogenesisofsynucleinopathies.HumMolGenet2003;12:2625-35.

35. CuervoAM,StefanisL,FredenburgR,LansburyPT,SulzerD.Impaireddegradationofmutantalpha-synucleinbychaperone-mediatedautopha-gy.Science2004;305:1292-5.

36. KraghCL,UbhiK,Wyss-CorayT,MasliahE.Autophagyindementias.BrainPathol2012;22:99-109.

37. ConwayKA,HarperJD,LansburyPT.Acceleratedinvitrofibrilforma-tionbyamutantalpha-synucleinlinkedtoearly-onsetParkinsondisease.NatMed1998;4:1318-20.

38. KosakaK.DiffuseLewybodydiseaseinJapan.JNeurol1990;237:197-204.39. CollaE,JensenPH,PletnikovaO,TroncosoJC,GlabeC,LeeMK.Accu-

mulationoftoxicalpha-synucleinoligomerwithinendoplasmicreticu-lumoccursinalpha-synucleinopathyinvivo.JNeurosci2012;32:3301-5.

40. HorvathI,WeiseCF,AnderssonEK,ChorellE,SellstedtM,BengtssonC,etal.Mechanismsofproteinoligomerization:inhibitoroffunctionalam-

yloidstemplatesalpha-synucleinfibrillation.JAmChemSoc2012;134:3439-44.

41. IwatsuboT.Pathologicalbiochemistryofalpha-synucleinopathy.Neuro-pathology2007;27:474-8.

42. SouzaJM,GiassonBI,ChenQ,LeeVM,IschiropoulosH.Dityrosinecross-linkingpromotesformationofstablealpha-synucleinpolymers.Implicationofnitrativeandoxidativestressinthepathogenesisofneuro-degenerativesynucleinopathies.JBiolChem2000;275:18344-9.

43. UverskyVN,LiJ,FinkAL.Metal-triggeredstructuraltransformations,aggregation,andfibrillationofhumanalpha-synuclein.Apossiblemo-lecularNKbetweenParkinson’sdiseaseandheavymetalexposure.JBiolChem2001;276:44284-96.

44. ConwayKA,RochetJC,BieganskiRM,LansburyPT,Jr.Kineticstabiliza-tionofthealpha-synucleinprotofibrilbyadopamine-alpha-synucleinadduct.Science2001;294:1346-9.

45. DanzerKM,HaasenD,KarowAR,MoussaudS,HabeckM,GieseA,etal.Differentspeciesofalpha-synucleinoligomersinducecalciuminfluxandseeding.JNeurosci2007;27:9220-32.

46. LashuelHA,OverkCR,OueslatiA,MasliahE.Themanyfacesofalpha-synuclein:fromstructureandtoxicitytotherapeutictarget.NatRevNeu-rosci2013;14:38-48.

Jee Eun Yang, Seung R. Paik · 2013-05-30 · HMR Jee Eun Yang, et al. • Amyloidogenic Protein of α-Synuclein Hanyang Med Rev 2013;33:123-129 질들이 선택적 상호결합에

Documents