672
86316470016778
Mustafa9459950234177327423544665765891
Taleb18949950234121242351459576
Ardah25289950234138296465590738
Department9451210014981156232313348384495569643679
of16611210014975112
Biochemistry1809121001495372147216285360471490535571606665
College9451354014989164183203277358433
of14151354014975111
Medicine156313540149110184264284353373446521
and21201354014981155236
Health23921354014974148229248285354
Sciences27831354014954123142217290359433478
Dissertation9441708017098132193255344389431524566599689773
Title94419630122426696120184
Screening18051905012050114145210275336356417484
For23171905012065130160
Novel25051905012090156211276296
Inhibitors28291905012039100161181249269303369399437
of32941905012082114
Αlpha-Synuclein345118820151723524190501202088149218251300354415476541561626646707
Seeded42581905012067132197265330399
Nucleation-Dependent46841905012091152216236301370404424489550583658723791856917985105011111145
Aggregation58571905012090158225255320387456490510575636
and18052025012068129198
Toxicity20312025012053119167187251271305359
as24172025012080119
a25632025012080
Potential26702025012071136170235296330350418438
Therapeutic31362025012053114179209278346411472506526590
Strategy3754202501206195125193227292359413
For41952025012059125155
Parkinson’s43772025012071139169219239300339404466501539
Disease49442025012085105144209278316381
Faculty9442178012248114178238262292350
Advisor13222178012274140196220264328360
Prof.1805218001205989154186213
Omar20462180012087181249279
El-Agnaf2353218001205474107181248309377409
Defense9442333012270134162226286330394
Date13662333012270136166230
1118052335012055111
December19432335012075140205270363432497527
201424972335012056111167222
Abstract9443648012274140184214246312376406
α-Synuclein18052636012144184926540962766109158207258274326342391
aggregation2262265409667121175199251304359386402455503
is278826540962859
the286926540963988140
key3031265409652104147
pathogenic3200265409667122149198250304356405421472
event3695265409664108160209236
in395326540962877
several405226540964395140192216270286
important4361265409628103157210234261315364391
neurological4775265409660112161185237253306359375427482498
disorders529526540966783114166190245297321352
including566926540962877129145193248264313367
Parkinson’s6058265409659114138178194243274327375403435
Disease,180527500966076107159213244296318
dementia2146275009663115190242291318334389
with256527500966783110159
Lewy274627500964597164207
bodies2975275009663116170186238269
and3267275009663112166
multiple3464275009675124140167183237253305
system379227500963982113140192267
atrophy,408227500966390114166221269312334
giving443927500966278122138187241
rise47022750096334980132
to485627500963688
a4966275009664
distinct505227500966379110137153202254281
group535527500966387139187242
of561927500966186
neurodegenerative5727275009658110158182234289341395447496548572627654670714766
diseases180528460965571102154208240292323
known215028460964796149215264
as243628460966293
synucleinopathies.255128460963982131179231247299315364416471525553601617669700723
Although329628460966682110158211259313362
the368028460963583135
molecular3845284609675128144196247296312367391
basis4258284609662117148164195
of447528460966085
α-syn45892828012144463328460962758100149
toxicity480428460963587126142194210237280
has5106284609656111142
not5270284609656109136
been5428284609662114166215
precisely566528460966286138189205236288304347
elucidated,603528460965975124175191246301328380435457
recent180529420962476128180228255
studies208329420964169117172188240271
indicate237629420962776131147199253280332
that273029420963987142169
α-syn29322924012144297629420962758100149
toxicity314729420963891129145197213240283
is345229420962758
mediated3543294209675127182198253280332387
by3952294209665108
a4082294209666
nu-cleation-dependent4170294209660108135187203255309336352405454480535587642694742797849898925
aggregation5117294209666120173198249303358385401453502
process.564129420966690142194246277308330
To599329420964593
elucidate610929420966278127179195250304331383
the180530380962776128
structural19553038096457296144196223272296351367
basis2344303809668122153169200
of256730380966591
α-synuclein26933020012144273730380962758100149198250266318334382
mediated3155303809675127182198253280332386
toxici-ty,356430380964093131147199215241268311333
we3920303809679131
developed4074303809668120164216232285339391446
various4542303809658112137153205254285
methods4862303809675127154203256310341
to522630380964093
prepare534130380966892143198253277328
different569230380966884109134186210262311338
α-synuclein60663020012144611030380962758100149198250266318334382
species180531340963186138189205257288
of211431340965277
a2211313409655
defined2286313409655107127146195247302
size26103134096294579131
and2761313409655103158
mor-phology2940313409675127151178232281333349402456498
distribution,345931340965470101129153169223272299315367416438
and3918313409654103158
we4096313409667119
investigated423731340961463107159190217233287341369421475
their473531340962574126142166
toxicity492331340962577116132183199227269
in521531340961463
different52983134096557196121173197249298325
human564331340964997172227276
dopaminergic5939313409655107162216291307356408432486502554
cell1805323009652104120136
lines.19633230096223887139170192
We2184323009677125
observed2331323009659113144196220265317371
that272532300963382136164
crude291132300965882131185237
α-synuclein31763212012144322132300962758100149198250266318334382
oligomers36263230096587490144197272324348379
preparations,402732300966185137191246270324352368420469500522
containing4571323009658111159187241257306322371425
both5018323009661113140189
monomeric5235323009675128177229304356380396448
and5705323009661110165
heterogeneous5892323009655107134186210262316368417469521570601
mixtures180533260967591129157205229281312
of213933260965883
α-synuclein22493308012144229433260962758100149198250266318334382
oligomers,26993326096577389143196271323347378400
were3127332609666118142194
the334333260963281133
most3504332609675127158185
toxic371133260963385124140192
species.392533260963691143194210262293316
The426333260963988140
toxicity442533260963385123139191207234277
of472433260965883
α-synuclein48343308012144487933260962758100149198250266318334382
aggregates5284332609660114167191243297352379431462
was5773332609667121152
directly594833260966076100152203230246289
linked62593326096223887127179234
to180534220962780
the190734220963584136
presence206534220966488139170222271323375
of246234220966186
the257034220963685137
monomeric2738342209675127176228303355379395447
α-synuclein,32163404012144326034220962758100149198250266318334382405
and3687342209663112167
strongly38763422096406791143192245261304
dependent4203342209663115170222270325377426453
on4678342209661110
its48103422096255283
ability4915342209663118134150166193236
in517334220962574
seeded526934220964092144198250305
nucleation-dependent5596342209658106158174226281308324376425452506558613665714769821869897
aggregation1805351809655108162186238292347374390442491
converting2321351809652105153198250274301317366420
into27633518096196895147
amyloid2936351809655130173189241257312
fibrils.32703518096234297121137153184206
Therefore349835180963887139163215240292316368
any3891351809655104147
effort406335180965277103155179206
to429235180963083
identify439735180961974126175202218243286
compounds4708351809652105180234287335384439470
that520035180963179134161
could5387351809652104153169223
inhibit563335180961968117133187203230
or588935180965276
even599135180965296148197
reverse621035180962880124176200231283
the180536140962776128
aggregation1955361409664117171195247301355383399451500
process247736140966387140191243274305
should280536140963988141189205260
assess308736140966495126178209240
the334936140963685137
effect350836140966186112164215242
of377336140966186
the388136140963685137
potential4040361409664116143195244271287342358
inhibitors442036140962573122138193209236288312343
on4786361409661110
the491836140963685137
seeded507736140964092144199251305
aggregation5405361409663117171195246300355382398450499
of592636140966287
α-synuclein,60443596012144608836140962758100149198250266318334382405
among1805371009655130182231285
others.211237100966693142194218249271
We2420371009676125
screened256737100964597121172224273325380
thirty296937100964190106130157200
Chinese3191371009679128144193245276328
herbal3541371009663115139194248264
medicinal3841371009675127182198250266315369385
compounds4249371009665118193247300348397452483
for475437100963992116
their489237100964190142158182
effect509637100966691116168220247
on5366371009666115
α-synuclein55163692012144556137100962758100149198250266318334382
aggregation,5966371009668122176200252306360387403456505527
seeded180538060963183135190242297
polymerization2124380609660112128171246298322338372427454470523571
and2718380609660109163
tox-icity290438060963285123150166217233261303
by3230380609660103
employing3355380609658133187203256298314363417
biophysical,379438060966076129183232275306322374429445467
biochemical428338060966076128180229281356372424478494
and4800380609660109164
cell-culture-based4986380609657109125141168219268284311360384436462517571602654709
techniques.571738060963385137186235251305354406437459
Among6204380609659134186235289
the180539020962776128
screened195539020963587111163215264316371
com-pounds,2348390209656108183210264317365414469500522
only2892390209657106122165
ginsenoside308339020965470119150202251303334350405457
Rb1,3562390209653107152174
salvianolic375839020963590106150166221270322338354406
acid4191390209654106122177
B,439039020965072
dihydromyricetin448939020965571119162217241293368411435451503555582598647
and5162390209655104159
gallic5347390209654109125141157208
acid5582390209655106122177
were5786390209666118142194
shown600239020963584137203252
to627639020963184
be6386390209655107
strong18053998096315882134183237
inhibitors206439980962977126142197213240292316347
of243339980966590
α-syn25583980012144260239980962758100149
fibrillation,277339980963252106131147163179233260276329377400
seeded319539980964395147202254309
aggregation3526399809667121175199251304359386402455503
and4052399809667115170
toxicity.424439980964092131147199215242285307
Our4585399809670118143
results475039980963688119168184211242
showed501439980964392145211263318
that535439980964088143170
gallic5546399809667121137153169221
acid,5789399809667119135190212
ginsenoside602339980966783131162214263316347363417469
Rb11805409409649103147
and1975409409660109164
salvianolic216140940963691107151167222271323339355407
acid2590409409661112128183
B2795409409652
inhibit286940940962270119135190206233
α-synuclein31294076012144317440940962758100149198250266318334382
fibrillation35794094096254499123139155171226253269321370
by3971409409660103
binding409640940966177125180196245299
and4417409409660109164
stabilizing460340940963764119173189205221255271320374
the499940940963382134
struc-ture51554094096366388136188215242290314366
of554340940965883
the564840940963382134
soluble,580440940963789105154208224276299
non-toxic6125409409654107155182209262300316368
oligomers,18054190096526884138191266318342373395
which2222419009679128144196245
are248941900966791143
devoid2654419009668120164217233287
of296441900966590
β-sheet30884172012141313041900962758106158210238
content.3390419009664117165193245293320343
In375541900963179
contrast,3857419009664117165192217271302329351
dihydromyrice-tin423141900966783132175230254306381424448464516568594621637686
was4939419009679134165
found512641900963891139188243
to539141900964092
be5506419009667119
able5647419009667122138190
to585941900964093
bind597441900966783132187
to618341900964092
both6297419009668120147196
oligomeric18054286096526884138191266318342358410
and2232428609655104158
monomeric2408428609675128176229304356380396448
species287842860962681133185201253284
of318042860965277
α-synuclein.32754268012144331942860962758100149198250266318334382405
In374642860961362
the383042860962372124
case3972428609651106137189
of417942860965277
gallic4274428609654109125141157208
acid,4500428609655107123177200
the472242860962271123
inhibition486742860961261110126180196223239292340
of522542860965378
α-synuclein53204268012144536542860962758100149198250266318334382
fibrillation57654286096203994118134150166220248264316365
is615242860961243
related62174286096197187142169221276
to180543820962780
the190743820963584136
compound’s2065438209660113188242295344392447475506
hydroxyl2593438209658101155179231270313329
moieties2952438209675128144196223239291322
whose3305438209666115167198250
number3578438209657105181235287311
and3911438209663112167
position4100438209663116147163190206258307
on4429438209661110
the456143820963684136
phenyl4720438209663111163212255271
ring50134382096334998151
were5195438209667119143194
proven541143820966388140184236285
to571843820963688
be5828438209663115
significant596543820964056110158174194213265320369396
for638343820963386110
the180544780962776128
process195644780965579131183235266297
of227644780965378
inhibition,237644780961766115131185201228244297346368
as276744780965586
indicated287544780961766121137189243270322377
by327644780965497
the339544780962977129
structure35474478096325983132183211259283335
activity3905447809655107134150194210237280
relationship42074478096267793148175191244292323372388443
data4673447809655110137191
obtained4888447809652107134188204253305360
from527044780962751103178
fourteen547044780962679127151179231283331
structurally58244478096325983132183210259283338354370413
similar625944780963248123139155210234
benzoic1805457409655107155189242258310
acid2137457409664115131186
derivatives.2345457409665117141157201256283299343395426448
Overall,2825457409670114166190245261277299
the314645740963685137
compounds3305457409662114189244296345393448479
identified380645740962681133181209225244264316370
herein4198457409659111135186202251
may4481457409675130172
represent467645740963385139163215246298347374
the507245740963786138
starting523245740964067122146173189238292
point5546457409664116132181208
for577645740963587111
designing5910457409664116147163217265281330384
new6316457409658110177
molecules1805467009675127143195247296312364395
that222246700963482137164
could2408467009659111160176230
be2661467009661113
utilized27964670096558298114130164216271
as308946700966192
drugs320346700966185134188219
for344446700963284108
the357446700963483135
treatment373146700963357109164191266318367394
of414746700965984
Parkinson’s4253467009654109133173189238269321370398429
Disease471146700965975106158213244296
and5029467009661110165
related52164670096308298153180232287
disor-ders.552546700966177108160185211266318342373395
Research9004949017081171232322414459549633
Relevance15724949017081171204294372465549638728
and23394949017093177269
Potential26474949017079168210300384426459552585
Impact32724949017039170263355445487
The90052020963483135
accumulation1054520209655106158207282331347401428444497545
of161952020965277
aggregated1715520209655109163187238292347374426481
form22185202096227599176
of241352020965378
α-synuclein25105184012144255452020962758100149198250266318334382
(α-syn)295952020962629855184012144303052020962758100149179
protein322852020965579131158210226275
in352552020961362
the360952020962473125
brain375352020965579133149198
has3970520209649104135
been4124520209655107159207
found435452020962274123172226
to460352020962476
be4698520209655107
the482752020962473125
main4971520209675130146195
characteristic5185520209652100155179234286313365389405436463479531
of573552020965277
Parkinson’s5832520209647102126166182231262314363391422
disease627352020965571102154209240292
and900529809655103158
related10805298096227490144171223278
disorders.137852980965571102154178232284309340362
Recent1759529809649101153205254281
studies206252980962855104159175227258
indicate234252980961462117133185240267319
that268352980962473128155
α-syn28585280012144290252980962758100149
toxicity307352980962577116132184200227270
is336552980961344
mediated3429529809675127182198252280332386
by383552980965597
a3952529809655
nucleation-dependent402652980964998150166218272299315368417443498550605657705760812861888
ag-gregation4934529809654108135189213264318373400416468517
process.547152980965478130182234265296318
Therefore581252980963180132156208233285309361
any6193529809654103146
effort635852980965278103155179207
to90053940962780
identify100253940961671123172199215240283
compounds1308539409651104179233286334383438469
that179953940962876131158
could1980539409652104153169223
inhibit222653940961665114130184200227
or247653940965277
even257553940965296148197
reverse279453940962577121173197228280
the309653940962877129
aggregation3247539409655109163187238292347374390442491
process376153940965478130182234265296
should407953940963281133182198253
assess435453940965586117169200231
the460753940962877129
effect475853940965277103155206234
of501453940965378
the511453940962776128
potential5265539409654107134186235262278333349
inhibitors563653940961665114130184200227280304335
on5994539409652101
the611753940962876128
seeded626753940963284136191243298
aggregation900549009655108162186238292347374390442491
of141254900965277
α-syn,15105472012144155554900962758100149171
among1748549009654129182230284
others.205354900965380129181205236258
Considering2332549009665117166197213268320344360409463
that281754900962675129157
many2995549009675129178221
potent3237549009655107134186235262
anti-amyloidogenic3520549009655104131147173228303346362414430485537591643692708760
agents4301549009655108160209236267
have4589549009649104148200
been4810549009655107159208
isolated50405490096154698114169196248303
from536554900962448100175
Chinese5561549009665114130179231262314
herbal5896549009649101125179234250
medicines6167549009675127182198250266315367398
(CHM),90055860963095149223252274
we1200558609667119
screened134155860963486110162214263315369
thirty17335586096307995119146189
CHM1948558609665119193
compounds,2166558609652105180234287335384439470492
for268055860962981105
their280755860963180132148172
effect300555860965277102154206233
on3264558609652101
α-syn33905568012144343555860962758100149
aggregation,3610558609655108162186238292346374390442491513
seeded414555860963587139193245300
polymerization4471558609654107123166241293317333367421449465517566
and5062558609655104159
toxicity524355860963083121137189205232275
by554455860965497
employing5667558609652127181197250293309357411
biophysical,610455860965470123177226269300316368423439461
biochemical90056820965571123175224276351367418473489
and1415568209654103158
cell-culture-based1599568209652104120136162214263279306354378430457511566597649704
techniques.232556820963183134183232248303351403434456
Among2807568209659134187236289
the311956820963079131
screened327256820963587111162214263315370
compounds,3668568209652104179234286335383438469491
only4185568209653101117160
ginsenoside437156820965470119150202251303334350405457
Rb1,4850568209652107151173
salvianolic504556820963590106150166221269322338354406
acid5477568209654106122177
B,567656820964972
dihydromycetin577356820965571120163218242294369412464516543559608
and6406568209655104159
gallic900577809654108124140156208
acid1131577809655107123177
were1331577809667119143195
shown154857780963281133199248
to181857780962881
be1922577809654106
strong20505778096325983136184238
inhibitors231057780961766115131185201228281305336
of266957780965277
α-syn27695760012144281457780962758100149
fibrillation,29855778096214095119135151167222249265317366388
seeded339557780963284136191243298
aggregation3716577809654108162186238292346373389442490
and4229577809655104159
toxicity.441057780962880119135186202229272294
Our4727577809670119143
results489257780962576107156172199230
showed514457780963281134200252307
that547357780962877131158
gallic5654577809654109125141157209
acid,5886577809654106122177199
ginsenoside610857780965470119150202251303334350405457
Rb1900587409649103147
and1070587409659108163
salvianolic125558740963691107151167222271323339355407
acid1684587409660112128182
B1889587409651
inhibit196258740962170119135189205232
α-syn22225856012144226658740962758100149
fibrillation24375874096254599123139155171226253269321370
by2829587409660103
binding295458740966076125179195244298
and3279587409655104159
stabilizing346058740963663118172188204220254270319373
the385558740963281133
structure40105874096366488136188215264288339
of437258740965782
the447658740963382134
soluble,463258740963688104153207223275298
non-toxic4952587409654106155181209261299315367
oligomers,53415874096587490144196271323347378400
which5769587409666115131183231
are602858740965478130
devoid6185587409655107152204220275
of648258740965783
β-sheet900595201214194159700962758106158210238
content.1197597009652104153180232281308330
In154959700961564
contrast,1631597009652105153181205259290317340
dihydromyricetin198959700965571120163217242294369412436452503555583599647
was2655597009666121152
found282959700962274123172227
to307859700962376
be3172597009655107
able3298597009654109125177
to349759700962476
bind359259700965470119174
to378859700962476
both3883597009654107134183
oligomeric40845970096536985138191266318342358410
and4512597009655104159
monomeric4689597009675128176229304356380396448
spe-cies515959700962782134161212228280311
of548959700965278
α-syn.55855952012144563059700962758100149171
In582459700961463
the590959700962473125
case6052597009652107138190
of626059700965378
gallic6357597009653108124140156208
acid,900606609655106122177199
the112260660963079131
inhibition127560660962069118134188204231247300348
of164960660965378
α-syn17536048012144179760660962758100149
fibrillation19686066096244398122138154170224251267320369
is235960660961951
related24326066096277995150177229284
to273860660963183
the284360660963180132
compound’s3001606609651104179233286334383438466497
hydroxyl352060660965396150174226265308324
moieties3870606609675127143195222238290321
whose4217606609667115168199251
number4490606609652101176231283307
and4822606609655104159
position5007606609654107138154181197249298
on5331606609652101
the545460660963180132
phenyl5611606609655104156205247263
ring58976066096274392146
were6069606609666118142194
proven628960660965478131175227276
to90061620962780
be1002616209654106
significant113061620963248101150166186205257312360387
for154061620962577101
the166361620962876128
inhibition181361620961665114130185201228244296345
process,218061620965579131183235266297319
as252161620965586
indicated262961620961665120136187242269321376
by302761620965598
the314761620962776128
structure32976162096315882131183210258283334
activity3653616209655107134150194210237280
relationship39556162096257692147174190242291322371387442
data4419616209655109136191
obtained4632616209653107134189205254306361
from501561620962549101176
fourteen521361620962578126151178230282330
structurally55666162096315882131182209258282337353369412
similar600061620963147122138154209233
benzoic6255616209654106155189242258309
acid900625809655106122177
derivatives.1104625809654106130146191245273289333385416438
Overall,1568625809670114166190245261277299
the188962580963280132
compounds2044625809656108183238290339387442473
identified253962580962175127176203219239258310365
herein2926625809653105129181197246
may3198625809675130173
represent339362580962880134158210241293342369
the378462580963180132
starting393862580963663117141169185233287
point4252625809654107123171198
for447362580962981105
designing4605625809655107138154207256272321375
new5002625809653105171
molecules5200625809675127143195247296312364395
that561762580963180135162
could5801625809656108157173228
be6055625809655107
utilized61846258096538096112128162214269
as647962580965586
drugs90063540965579128181212
for113563540962678102
the125963540962877129
treatment141063540962852104159186261313362389
of182263540965277
Parkin-son’s1922635409648102127167183231258289341390418449
disease239563540965470101153208239291
and2709635409655104158
related28906354096257692147174226281
disorders.319463540965571102154178233285309340362