Imbali yeeNgxaki zokuHamba: Iimodeli zezilwanyana zokufunda ngesifo sikaParkinson

Njengoko sisazi, uphando lwesifo sikaParkinson luxhomekeke kwiimodeli zezilwanyana kangangeminyaka engaphezu kwesiqingatha senkulungwane. Nangona kunjalo, siyazi ukuba akukho modeli inye echaza ngokupheleleyo isifo somntu. Kwaye namhlanje siza kujonga emva kwindlela ezi modeli ezavela ngayo, oko zasifundisa kona, oko zisilele ukusifundisa kona, kunye nokuba eli candelo liya phi.

Kwaye ngenxa yoku, ndinovuyo lokuba noGqr. Franziska Richter-Assêncio ovela kwiYunivesithi yeZilwanyana eHanover, eJamani, kwaye uyintloko yeSebe lezeMithi kunye neToxicology, kunye noGqr. [00:01:00] uJeff Kordower, umlawuli osungula i-ASU Banner Center kwiYunivesithi yaseArizona State eMelika.

Enkosi nobabini ngokundijoyina. Ndonwabile kakhulu ukuba neenkokheli ezinjalo kwicandelo lophando lwesifo sikaParkinson kunye neengcali kwiimodeli zezilwanyana, ngoko ke oku kuza kuba luncedo kakhulu kubaphulaphuli bethu. Kwaye ndifuna ukuqala ngombuzo osisiseko. Kutheni ke ngoku sifuna iimodeli zezilwanyana?

Yile nto sifuna ukuyazi. Ukuba besinokubuyela emva kwiminyaka embalwa eyadlulayo, yintoni ababeyazi abaphandi, kwaye kutheni iimodeli zezilwanyana zazithathwa njengezibalulekileyo kuphando lweParkinson's? Ngoko ke Jeff, mhlawumbi ungahamba kuqala.

UNjingalwazi uJeffrey Kordower: Ngoko ke kukho izizathu ezininzi zokuba kutheni sifuna iimodeli zezilwanyana. Okokuqala kukuba, ukuba siza kuphuhlisa unyango olutsha, kufuneka siqinisekise ukuba lukhuselekile kwaye lusebenza kakuhle kwaye luyanyamezela, kwaye singenza ezo zifundo kwiimodeli zezilwanyana. Esasicinga ekuqaleni kukuba isifo sikaParkinson yayisifo se-dopamine, isifo sokuwohloka kwe-nigrostriatal.

Ngoko ke [00:02:00] iimodeli ezaphuhliswayo yayizizilonda ze-6-hydroxydopamine kwiimpuku. Ekugqibeleni, emva kokufunyanwa kwe-MPTP kwizilwanyana ezingengobantu, i-MPTP yaba yimodeli. Kodwa ezi modeli, ngoku siyazi ukuba isifo sikaParkinson, ngokomthetho, sisifo esihambisanayo. Kukho izinto ezininzi ezingalunganga kwiingqondo zezigulane ezinesifo sikaParkinson.

Ngoko ke kufuneka sitshintshe iinkqubo zethu zokumisela ukuze zifane ngakumbi noko kwenzekayo kwizigulana ezinesifo sikaParkinson. Elinye lamanyathelo okuqala amakhulu kuloo ndlela yayingumsebenzi mna noPatrik Brundin esawenzayo ekufumaniseni ukuba i-alpha-synuclein pathology yenzeka ekufakelweni kwezicubu kwizigulana ezinesifo sikaParkinson.

Oko kwakhokelela ekubeni uVirginia Lee kunye nabalingane bakhe babonise ukuba ii-fibrils ze-synuclein ezandulelayo zayimodeli ye-synucleinopathy ebonakala kakhulu kwizigulane ezininzi, [00:03:00] kodwa kungekhona zonke izigulane ze-PD. Ngoku siyazi ukuba i-tau ngumdlali omkhulu kwi-pathology yesifo sikaParkinson, ngoko ke siphuhlisa iimodeli ze-co-pathology apho izilwanyana ziya kuba ne-synuclein, i-tau, kunye ne-amyloid, kuba ezo zezona zifo zintathu zinkulu.

Kwaye siyazi ukuba xa usenza i-co-pathologies, oko kuyayiphucula i-pathology kwaye kuyayiphucula imiba yezonyango kwezi zilwanyana kwaye ziba nzima ngakumbi. Kwaye ke ezi zizinto ezenzekayo ngoku.

UNjingalwazi Tiago Outeiro: Enkosi, Jeff. Ngoko ke, sele unike umbono omangalisayo wokuba sivela phi kwaye siya phi. Kodwa uFranziska mhlawumbi ungahamba inyathelo ngenyathelo kwinto esilindele ukuba ii-m-models ziyimodeli. Singalindela ukuba ziyimodeli ye-pathology njengoko uJeff wayethetha ngayo, kodwa kukho nezinye iinkalo zeParkinson esingathanda ukuzimodeli nazo.

Ungacacisa kancinci ngale nto? 

UNjingalwazi uFranziska Richter Assêncio,: Ewe. Ngoko ke, uJeff sele [00:04:00] esenze isishwankathelo esihle kakhulu, akunjalo? Kuzo zonke iimodeli ezahlukeneyo, kwaye ndicinga ukuba okwacacayo kukuba ezinye iimodeli zazibaluleke kakhulu ukuphinda iimpawu. Ngoko ke sizibiza ngokuba ziimpawu kwiimodeli ngokwenene, kodwa nakwi-pathology. Emva koko siye saya phambili kwindlela yokusebenza. Kwaye into onokuyenza ngemodeli, ungacinga ngokunyaniseka.

Ngoko ke into esiyenzayo, sicinga ngokuqinisekiswa kwesakhiwo, ukuqinisekiswa kobuso, kunye nokuqinisekiswa kwangaphambili. Ngoko ke ukuqinisekiswa kwesakhiwo kuthetha ukuba imodeli kufuneka isondele kangangoko kunokwenzeka kwisizathu sokwenyani sesifo. Ngoko ke ukuba ndisebenzisa ityhefu engasayi kuze ingene engqondweni yomntu, ngoko ke oku akulona ukuqinisekiswa kwesakhiwo okulungileyo.

Nangona kunjalo, ukuba ityhefu itshabalalisa ii-neurons ze-dopaminergic, kule meko, inika ukuqinisekiswa kokwakhiwa kwayo kwinqanaba elithile, kwaye into eza kuyinika kukutshintsha kweempawu, iimpawu. Iya kunika iimpawu ze-Parkinsonism, kwaye oko kukuqinisekiswa kobuso okuhle. Ngoko ke ukuqinisekiswa kobuso kuya kuba ziimpawu, iimpawu ezikwimodeli.

Kwaye [00:05:00] zombini eneneni, ukwakheka kunye nokusebenza kobuso kubalulekile ekuphuhliseni amayeza kuba iyeza liya kujolisa kwinto ethile ekuqinisekisweni kokwakhiwa. Ngethemba liya kunceda ii-neurons ukuba ziphile, okanye liza kuthatha indawo ye-dopamine, kwaye emva koko liya kutshintsha kwaye lenze iimpawu, ubuncinane ziphucule iimpawu, iimpawu ezikwimodeli.

Kwaye ngokufanelekileyo ke ngoko sinokuqinisekisa ukuba izinto ziya kwenzeka. Kwaye umntu kufuneka athi kwezo ndlela zonyango ezineempawu ezaphuhliswa ngeminyaka yoo-1970 nangolwazi oluvela kwiminyaka yoo-1960, njenge-levodopa, esengumgangatho wegolide, sisebenzise ezo modeli zazibangelwa bubuthi kwaye zazinobuso obuhle, kwaye zazinobungqina obuhle kakhulu bokuqikelela ukuba izinto ziya kwenzeka xa kuthe kwabakho i-dopamine replacement therapy kunye ne-levodopa-induced dyskinesia.

Kodwa ngoku, njengoko sele uvile kuJeff, sihamba kakhulu ngaphaya koko, kwaye sihamba kakhulu ukuya kwiindlela kunye neeproteni kunye nokuhlanganiswa kwezifo ezidibeneyo kunye nazo zonke ezo zinto. Kwaye kwezo modeli azizo iimodeli ezifanelekileyo zokuzisebenzisa kuloo nto. Kufuneka [00:06:00] siye kwiseti yemodeli, sibonise ngqo ezo mpawu zokwakha, kwaye ngethemba lokuba ziya kuba nobuchule bokuqikelela kwinqanaba elithile lokuphuhlisa unyango oluguqula izifo.

Umzekelo, yenza ukuba isifo siqhubeke kancinci.

UNjingalwazi Tiago Outeiro: Ewe. Enkosi. Ngoko ke sele sive okuninzi malunga neentlobo ezahlukeneyo zeemodeli, iimodeli ezisekelwe kwityhefu, malunga nezinye iimodeli ezisekelwe kwimfuza, kunye nezinye iimodeli ezisekelwe kwizifo ezisasaza izifo uJeff aye wazivelisa waza wazikhankanya.

Sineemodeli ezininzi. Sikwanabaphulaphuli abaninzi kwi-podcast yethu, uninzi lwabaphulaphuli bethu lukwangoososayensi kwaye basebenzisa iimodeli kuphando lwabo. Ngoko ke kuyadida kakhulu xa ucinga ngeemodeli zeParkinson kuba kukho amakhulu eemodeli umntu anokukhetha kuzo ukuze azisebenzise.

Akukho modeli zezilwanyana ezincancisayo kuphela, kodwa ezo zezo sizigubungelayo apha namhlanje, kodwa singathetha nangeemodeli zeempukane, okanye iimodeli zeempethu. Kodwa namhlanje sigxile kwiimodeli zezilwanyana ezincancisayo kwiimpuku, iimpuku, kunye nee-primates ezingezizo ezomntu. [00:07:00] Ngoko ke nokuba sicinga nje ngezi zilwanyana, zininzi kakhulu. Ngoko ke sifanele sicinge njani malunga nokuba yeyiphi imodeli engcono? Yeyiphi imodeli ekufuneka isetyenzwe yintsimi? Kukho into enjalo? Ngaba intsimi kufuneka isebenzise imodeli enye, okanye intsimi kufuneka isebenzise iimodeli ezininzi? 

UNjingalwazi uJeffrey Kordower: Ngoko ke iimodeli ezininzi zihlala zingcono. Kodwa ndicinga ukuba kufuneka uchaze ukuba nguwuphi umbuzo owubuzayo. Ngoko ke sisebenzisa iimodeli ezisekelwe kwityhefu, sikwazile ukuphuhlisa i-levodopas, njengoko uGqr. Richter esithi ngumgangatho olungileyo, kunye nokukhuthaza ubuchopho nzulu. Kodwa ziya kuchaphazela kuphela iimpawu ze-cardinal motor.

Kodwa kufuneka uchaze into oyifunayo ngokwenene. Ngoku, izinto ezimbini ezifaka abantu kwiindawo zokugcina abantu abadala yi-dementia kunye nokuwa, kwaye loo nto ayisiyonto i-nigrostriatal function. Ngoko ke kufuneka uye kwezinye iintlobo zeemodeli, kwaye ndiziva ndinethemba kakhulu ngeemodeli ze-co-pathology kuba zizisa i-tau kunye ne-amyloid ekusebenzeni. Enye kukuwa. Ngoko ke imiba yokulinganisela ifaka abantu kwiindawo zokugcina abantu abadala kuba [00:08:00] bayawa, bayaphuka isinqe, abaze baphile, njengoko babenjalo ngaphambi kokuwa. Ngoko ke okokuqala, ufuna ukuchaza ukuba ngumbuzo onjani ofuna ukuwubuza. Ukuba ufuna ukulandela ulwazi, i-6-hydroxydopamine, MPTP, ayibalulekanga, ngoko ke andinakucinga ngaloo nto.

Kodwa ke ngoko kuya kufuneka ndiye kwelinye icala. Enye into endifuna ukuyichaza, oko akuthethi ukuba iimodeli zetyhefu azinamsebenzi, kuba ubunzima ngezi modeli zezinye kukuba azidali izilonda ezinkulu njengeemodeli zetyhefu. Ngoko ke awunakubangela i-dyskinesias usebenzisa i-alpha-synuclein preformed fibrils okanye, okanye ezinye iintlobo zokuhanjiswa kwe-synuclein. Ngoko ke ngoku senza izifundo zokuphelisa i-dyskinesias kwiinkawu ngonyango lwe-gene lwe-Cav1.3. Bendingenakukwenza oko ukuba bendisebenzisa nje iimodeli ze-synuclein. Ngoko ke, okokuqala, ufuna ukwazi ukuba yintoni i-pathology kwizigulane kwaye wazi ukuba zeziphi iimodeli ezijongana neempawu ze-[00:09:00] ozifunayo ngokwenene. 

UNjingalwazi Tiago Outeiro: Enkosi. Kwaye uFranziska ugxile ngoku kwiimodeli zemfuza, ozisebenzisileyo kakhulu kunye neemodeli ze-synuclein transgenic, ungasinika umbono omncinci wokuba eli candelo laqala nini kwaye siphi okwangoku, kwaye zeziphi iimodeli umntu afanele aziqwalasele?

UNjingalwazi uFranziska Richter Assêncio,: Ewe eneneni umntu ungathi yaqala ngokufunyanwa, akunjalo? Ngendima ye-alpha-synuclein, eyayingo-1997. Ukususela ngoko bekukho ithemba elikhulu. Ukuba nditshintsha i-alpha-synuclein kwimpuku, kwimpuku, ndiza kufumana imodeli efanelekileyo kwaye ndingayisebenzisa. Kwaye ekuqaleni yayidanisa kancinci kuba kanye njengoko uJeffrey Kordower esandula ukutsho, yingxaki.

Azilahlekelwa zii-neurons kangako njengoko besiqhelene nazo kwiimodeli zetyhefu. Kodwa bekulindeleke ekuqaleni, akunjalo? Ngoko ke abaphandi baqala ukukhupha i-alpha-synuclein eninzi, i-alpha-synuclein eguquliweyo kwaye abazange bafumane lahleko ingako yee-neurons ze-dopaminergic. Iimodeli ezininzi zabuyiselwa kwidrowa.

Kwaye ngelo xesha ngo-2007 xa ndandijoyina ilabhoratri kaMarie-Françoise Chesselet [00:10:00], kwaye kwakukho noSheila Fleming, babesebenza nemodeli ekhupha i-alpha-synuclein kakhulu. Kwaye ezi impuku, zithatha de zibe neenyanga ezili-14 ubudala ngaphambi kokuba zilahlekelwe yi-dopamine. Kwaye abaphandi abaninzi babenokuzibuyisela ngqo kwidrowa, kodwa azizange, kwaye thina asizange, kwaye saqhubeka nokuchaza, kwaye safumana ukuhlanganiswa kwe-alpha-synuclein, inkqubela ecothayo, ukudumba, iimpawu ze-non-motor, motor.

Saya ngaphaya koko sajonga amanqanaba okukhula kweseli. Ngoko ke intsimi yatshintsha ngokwenene. Kodwa saqonda ukuba sisafuna iimodeli apho silahlekelwa khona ziiseli. Ngoko ke abantu baphuhlise ezinye iimodeli ezifana neemodeli ezazinotshintsho.

Emva koko intsimi yafudukela kwi-fibrils ezazenziwe ngaphambili, ezazinxulunyaniswa nokufunyanwa okanye ingcamango yokuba i-alpha-synuclein yiproteni efana ne-prion kwaye inokusasazeka, isifo sinokusasazeka.

Ngoko ke oku kwayitshintsha ngokwenene intsimi kwakhona. Kodwa nganye kwezi modeli iphendula umbuzo othile. Njengemodeli ye-preform [00:11:00] ye-fibril ngokuqinisekileyo yimodeli yokwenziwa, akunjalo? Kuba akwenzeki kwisigulana ukuba umntu ayifake engqondweni, kodwa iphinda isifo esithile. Kwezinye iimodeli kukhokelela ekuvuvukeni, kodwa akusiyo ukuvuvuka okunamandla.

Abantu badla ngokuthi abafumani zifo ezininzi ze-neurodegeneration ngale modeli. Oko akuthethi ukuba ufanele ungayinaki kuba isaphinda-phinda isifo, kwaye ungayisebenzisa ukuvavanya amayeza okanye ukuphuhlisa amayeza amatsha aphazamisa ukuhlanganiswa kwe-synuclein kunye nokusasazeka kwayo. Ngoko ke yonke imodeli inendima yayo kuyo.

Kunjalo nakwiimodeli ze-AAV. Zinzima kakhulu. Ukhupha i-alpha-synuclein kakhulu ngokufaka i-AAV kwi-substantia nigra, kodwa apho ufumana ukulahleka kweeseli, kwaye ufumana ukudumba okukhulu. Ufumana ukuphazamiseka komqobo wegazi-ubuchopho. Ngoko ke, ngesizathu esithile, usenokugqiba ekubeni usebenzise le modeli. Ngoko ke, kum eyona modeli ilungileyo yimodeli echazwe kakuhle, kwaye umphandi osebenzisa le modeli [00:12:00] uyazi okuninzi ngayo, uyichaze, uyaqonda indlela i-pathology enxulumene ngayo nesayensi, kunye noko inokukuxela kwangaphambili malunga nonyango. Ngoko ke, ngokwenene sisixhobo, kwaye malunga nendlela osiphatha ngayo eso sixhobo kunye nolwazi onalo lokusingatha eso sixhobo.

UProfesa Jeffrey Kordower: Into enye, ukuba ndingangena nje ngokukhawuleza, yimodeli abantu abangasebenzisi ngokwaneleyo. Kwaye isifo sikaParkinson sisifo esinxulumene nobudala, esibangela ukonakaliswa yimithambo-luvo, kwaye asisebenzisi izilwanyana ezindala ngokwaneleyo. Ndizisebenzisa, kwizilwanyana ezingengobantu, kwaye zine-amyloid yendalo. Ngoko ke, uyazi, naziphi na izinto endinokuzisebenzisa, zisenayo inxalenye ye-co-pathology endiyichazayo, iimpawu kunye ne-pathology yezigulane zikaParkinson ezindala.

UProfesa Tiago Outeiro: Ewe. Enkosi, Jeff. Oku kundizisa kwingongoma ebalulekileyo, ewe, iimodeli zeempuku zinezibonelelo ezininzi kuba kulula kakhulu ukuzigcina kwindawo yezilwanyana. Azithathi ndawo ingako, kodwa kusekho ixabiso elikhethekileyo kwiimodeli ze-[00:13:00] ezingezizo zabantu. Kwaye ngeli xesha siva abantu abaninzi bebuza ukusetyenziswa kwezilwanyana njengeemodeli zophando, ngaba sisenokuthethelela ukusebenzisa izilwanyana ezifana nee-primates ezingezizo zabantu kolu hlobo lophando? Ngaba siyazidinga, okanye sikwinqanaba apho singazitshintsha khona?

UProfesa Jeffrey Kordower: Enkosi ngokundinika ithuba lokuphendula loo mbuzo. Ndicinga ukuba kubaluleke kakhulu, sidinga iiprimates ezingezizo zabantu. Ndicinga ukuba, okokuqala, ubuchopho bazo bukhulu, ingakumbi xa usenza unyango. Uyakwazi ukufumana okuninzi-- ukufunda okungcono, ngeeprimates kuneempuku ezingenayo i-prefrontal cortex, ngoko ke kunzima ukwenza ulwazi kwiimpuku. Ukuba ufuna ukuqonda, ndicinga ukuba iiprimates ezingezizo zabantu zibalulekile. Mna noJohn Marsden senze imodeli ye-tauopathy kwiinkawu endicinga ukuba yeyona modeli ye-tauopathy ilungileyo ekhoyo, ngoko ke siyakwazi ukufumana ii-co-pathology ukuze zihlole zombini i-pathogenesis kunye ne-therapeutics. Ngoko ke ndicinga nokuba ngexabiso le-[00:14:00], nangona nezinye izinto ozikhankanyileyo, Tiago, ndicinga ukuba kubalulekile ukuba sisebenzise iiprimates ezingezizo zabantu njengendlela yokungena kwizilingo zeklinikhi kunye nezigulane.

UProfesa Tiago Outeiro: Ewe. Enkosi. Ndifuna ukucacisa kakhulu ngalo myalezo kuba kukho umkhwa wokucinga ukuba singayilinganisa isifo esintsonkothileyo sisebenzisa ezinye iintlobo zeemodeli, esizamkelayo sonke ukuba ziluncedo kakhulu kwezinye iintlobo zezifundo, kodwa kukho imibuzo ekufuneka ijongwe kusetyenziswa ezi ntlobo zeemodeli.

Ngoko ke lo ngumyalezo ocacileyo esifanele siwudlulise. Kwaye Franziska, bendifuna nokuthetha ngesinye isihloko esibucayi kweli candelo, esithi, mhlawumbi sonke asilunganga kwaye i-pathology, i-synuclein pathology, okanye i-protein pathology ayiyondlela ilungileyo. Mhlawumbi into ekufuneka siyiqwalasele kukulahlekelwa ngumsebenzi, i-proteinopenia.

Kodwa sinobungqina obuninzi obuvela kwezi modeli obuxhasa ingcamango yokuba kukho into engalunganga, enxulumene nokuqokelelwa kwezi protein. Ungasinika ulwazi oluthile [00:15:00] malunga noko sikufundileyo kwezi modeli zezilwanyana oluxhasa le ngcamango yokuba mhlawumbi intsimi ayisiyonto iphambeneyo? Asiyazi inyaniso.

Asazi ukuba yintoni ebangela izifo, kodwa kukho ubungqina obuninzi obuxhasa ingcamango yokuba i-protein pathology isenokuba ibaluleke kancinci.

UProfesa Franziska Richter Assêncio,: Ewe. Ngoko ke njengososayensi uyazi ukuba akukaze kube mnyama okanye kube mhlophe, akunjalo? Ndicinga ukuba zombini ziyinyani ngandlela thile. Sinemodeli zezilwanyana xa sikhupha i-alpha-synuclein kakhulu, njengokuba ukuphindaphinda kwe-alpha-synuclein kunokubangela iParkinson, akunjalo? Okanye ukuguqulwa kwe-alpha-synuclein kunokubangela iParkinson yosapho.

Singakwenza oku kwiimodeli, kwaye sinokuphinda uninzi lwe-pathology kwisayensi. Oku akuthethi ukuba akukho lahleko yomsebenzi we-physiological weproteni ekhoyo ngokwenene, kwaye sinokubona ubungqina boko nakwimodeli. Yindibaniselwano. Unelahleko ethile enxulumene mhlawumbi [00:16:00] kwiimpawu ezithile, enxulumene mhlawumbi nakwizigaba ezithile zesifo, kodwa ngokuqinisekileyo unayo i-aggregation.

Kwaye into enye endingayi kuyithetha ngenxa yokuba mhlawumbi ulahlekelwe kancinci, akunjalo? Andiyi kubeka i-alpha-synuclein engaphezulu engqondweni njengonyango. Apho ndicacile kuba ngalo lonke ixesha sinyusa i-alpha-synuclein nakweyiphi na imeko, umzekelo weseli okanye nantoni na, ayisiyonto ilungileyo.

Kusoloko kunjalo ukuba unayo loo protein ininzi, kwaye oko kukwanjalo nakwezinye iiproteni ze-amyloid, iyanda, kwaye ihlangana ukuya kwinqanaba elithile. Kwaye ngokwenene sikwacinga ukuba lo ngumsebenzi we-alpha-synuclein. Ayisiyompazamo yokuzivelela. Ikwenza oku mhlawumbi ukuthintela ezinye izifo.

Ngoko ke i-neuroinfection luphando olukhulu kwilebhu yam apho sibonisa khona ukuba i-alpha-synuclein iyanda ekubonakaleni kwayo ukuba unezifo ezithile zentsholongwane. Kwaye ke ithanda ukuhlangana. Yakha imiqobo efana [00:17:00] ngokusisiseko ukuze ezo ntsholongwane zingene okanye zenze i-pathology yazo. Ngoko ke iyinto yomzimba, kodwa ukuba uyongeza ngaphandle ngaphandle okungalawulwayo, yona-- kum, iya kwandisa i-pathology, i-co-pathology. Ngoko ke, ndicacile ngokwenene. 

UNjingalwazi uJeffrey Kordower: Ndicinga ukuba yayilimpendulo egqibeleleyo, ngokweembono ezahlukeneyo. Endingathanda ukuyongeza kukuba ukuba sinazo ezi zifo zidibeneyo kwaye sinazo ezi protein zisasazekayo, ngoko ke siza kuhlasela ntoni ngokweembono zonyango? Ngaba kunengqiqo ukuzama ukunciphisa i-alpha-synuclein xa usenayo i-tau kunye ne-amyloid kunye ne-TDP-43?

Ngoko ke into eyenziwa yilebhu yam kukujonga iindawo apho une-nidus yazo zonke izifo. Umsebenzi we-Lysosomal, oya kususa zonke iiproteni ezigobileyo. Ukudumba kwenzeka kuzo zonke izifo ze-neurodegenerative kwaye kubandakanyeke kuzo zonke, ii-proteinopathies. Ngoko ke sifunda nge-irisin, eyiproteni esiyaziyo ukuba iya kunciphisa i-synuclein, i-tau, kunye ne-[00:18:00] amyloid. Kwaye senza oku ngoku kwi-primate engeyomntu esandula ukufumana inkxaso-mali yokwenza oku. Sivuya kakhulu ngale nto. Kodwa ndicinga ukuba isigqibo sokuya kunyango kufuneka siqonde i-pathology yokwenyani esebuchotsheni bezigulane zikaParkinson. Kuchithwe amakhulu ezigidi zeerandi ukuzama ukunciphisa i-alpha-synuclein, kwaye nokuba uphumelele, amathuba okuba nenzuzo enkulu yeklinikhi mancinci.

Umzekelo, thatha indawo ye-Alzheimer's, apho une-immunology, la ma-antibodies anokususa i-amyloid. Uh, w- aboniswe kwi-PET ngokungangqalanga, kodwa umgangatho wenzuzo yokusebenza awunto yanto kwixesha elide. Ngoko ke ukuqonda isifo se-pathology uze usisombulule ngonyango lonke, ndicinga ukuba kubaluleke kakhulu ukuya phambili. 

UNjingalwazi Tiago Outeiro: Ewe, kwaye uJeff uh, mna noFranziska singabelana nawe ngengxaki yakutshanje ngeprojekthi eyayijolise [00:19:00] ukujonga iingxaki ezihambisanayo kodwa engaxhaswanga. Kodwa loo nto yingongoma yelinye ibali.

UProfesa uJeffrey Kordower: Yiza eArizona.

UNjingalwazi uFranziska Richter Assêncio,: Kulungile. Besifuna ukwenza i-synuclein, i-tau, kunye ne-TDP-43, kwaye besineqela elikhulu kakhulu. Kodwa ewe, iJamani yayingekakulungeli oku, ndicinga.

UNjingalwazi Tiago Outeiro: IJamani ayifumani thuba kulo loliwe. Iyawuvumela ukuba udlule, kwaye lihlazo. Kodwa ke, ukuze sixoxe kutshanje, ndingathanda ukubuyela kwinkalo yokuziphatha yokusebenzisa iimodeli zezilwanyana, kuba oku kubaluleke kakhulu. Andifuni ukuba lula koku. Ndifuna ukucela ngamnye kuni ukuba athethelele abaphulaphuli bethu abanokuba nexhala ngezinto esizenzayo kwilebhu, malunga nendlela esinokuthetha ngayo ukusebenzisa izilwanyana kuphando esifuna ukulwenza.

UProfesa Jeffrey Kordower: Okokuqala, awunakwenza nto kwisilwanyana [00:20:00] ngaphandle kokufumana imvume esiyibiza ngokuba yi-institutional, IACUC. Le komiti ye-IACUC yenziwe ngoogqirha bezilwanyana, abantu abaqhelekileyo, izazinzulu, kunye nezigulane. Ngoko ke, uthi, "Ndiza kwenza u-X, u-Y, kunye no-Z." Ungenza u-X, u-Y, kunye no-Z kuphela. Kwaye kufuneka wenze yonke into ngobuntu kangangoko kunokwenzeka, kwaye yiloo nto le komiti eyenzayo, kwaye kukho ulwalathiso lolu hlobo lwento. Ngoko ke ndenza umsebenzi wam omninzi ngee-primates ezingezizo ezomntu. Ndijongwa ngokukodwa, nto leyo ilungileyo kum. Kwaye sizama ukunciphisa uxinzelelo kunye nentlungu kuyo yonke inyathelo endleleni.

UNjingalwazi Tiago Outeiro: Kwaye uFranziska, ukwisikolo soogqirha bezilwanyana, ngoko ke ujongana nale micimbi kakhulu.

Awujongi nje kuphela uphando lwakho, kodwa nophando olwenziwa ngabanye abantu besebenzisa iimodeli zezilwanyana. Ngoko ke uthini umbono wakho? Ewe, ndiyazi ukuba uyaluxhasa uphando lwezilwanyana kodwa sifanele silujonge njani olu [00:21:00]?

UNjingalwazi uFranziska Richter Assêncio,: Ewe. Ngamanye amaxesha ufumana ingcamango yokuba yingcamango entsha, kodwa ingcamango ye-3R ivela ngo-1959, kwaye ibisetyenziswa ukususela kwixesha elide. Ngoko ke nciphisa, phucula, tshintsha. Ngoko ke nciphisa, sebenzisa izilwanyana ezimbalwa. Sebenzisa izilwanyana ezininzi kuphela njengoko kufuneka, kubalulekile kumbuzo wakho wophando. Coca, ngoko ke ngaba wakho, umzekelo, usebenzisa amayeza okuthomalalisa iintlungu, akunjalo?

Ngoko ke izilwanyana azinantlungu. Kwaye zitshintshe. Ngoko ke ukuba awudingi ukusebenzisa isilwanyana, ukuba ungasebenzisa inkcubeko yeseli okanye i-organoid, uyayenza loo nto. Kwaye abaphandi bakwenzile oko kuba akukho mntu usebenzisa isilwanyana okanye isilwanyana esiphuhliswe ngokukodwa ukuba akufuneki, akunjalo? Kwaye besikwenza oku ixesha elide, kodwa kuye kwasebenza ngakumbi ngoku kwaye kukho imithetho ethile kunye neekomiti njengoko sele sivile.

Kodwa into endifuna ukuyongeza kukuba, luphando olucwangcisiweyo kakuhle apho isilwanyana sisempilweni ngaphandle kwesifo esichazwe ngokuchanekileyo kunye nemeko othanda ukuyilinganisa, akunjalo? Ngoko ke isilwanyana [00:22:00] sisempilweni ngaphandle koko. Oko kuzuzisa zombini, njengentlalo-ntle yesilwanyana kunye nomgangatho wesayensi wophando lwakho.

Ngoko ke kule nkalo, impilo-ntle yezilwanyana kunye nenjongo yesayensi, zihambelana kakhulu, kwaye oku sele kuyinto ebalulekileyo ukuyiqonda. Kwaye nemigangatho yokuziphatha ngokubanzi, ayimiselwanga phantsi, akunjalo? Le yinto eguqukayo ngesayensi, ngemilinganiselo onayo kuluntu.

Ngoko ke okubalulekileyo kukuba kufuneka siqhubeke sithetha ngezinto esizenzayo apha, malunga nokuba kutheni sisebenzisa iimodeli zezilwanyana. Kwaye ndikholelwa ukuba imibutho yezigulane inokuba negalelo elikhulu kuloo nto kuba ingasinceda thina zizazinzulu. Ndingathetha ngokwembono yesazinzulu, kodwa uninzi lomsebenzi esiwenzayo, lukhokelela kwinqanaba elithile kunyango, akunjalo?

Kuphuhliso lwezonyango, kwanophando olusisiseko. Kwaye kungangcono ukuba kukho unxibelelwano olungakumbi oluvela kwimibutho yezigulana ukuze uluntu, uluntu luqonde kwaye, lusixhase ekwenzeni olu phando [00:23:00].

UNjingalwazi uJeffrey Kordower: Ndingagxininisa into endicinga ukuba uGqr. Richter uthe ibaluleke kakhulu kwaye ngamanye amaxesha iyalahleka? Nciphisa. Kwaye uthe ngokuchanekileyo, nciphisa ukuya kwinani elincinci lezilwanyana onokuphendula umbuzo wakho. Kusafuneka unikwe amandla afanelekileyo. Ndihlaziya amaphepha amaninzi apho abantu banenkawu enye okanye ezimbini, kwaye banamandla angaphantsi ngokupheleleyo, baze bathi, "Ewe, kufuneka sinciphise inani lezilwanyana."

Oko kukudlala ngeenkawu kuba awunayo eyaneleyo yokuphendula lo mbuzo. Ngoko ke ndicinga ukuba oko uGqr. Richter akuthethayo kubaluleke kakhulu. Yehlisa uye kwinqanaba apho usenokuwuphendula khona lo mbuzo, kodwa yehlisa kangangoko unako.

UProfesa Franziska Richter Assêncio,: Ewe, abanye abantu bathi, "Kutheni ningasebenzisi ii-organoids? Zifana nesitya. Unengqondo esityeni." Kodwa ewe sele sikwenza konke oku kangangoko sinako, akunjalo? Sineeseli zabantu. Siyazihlola. Sijonga iindlela zofuzo. Senza konke oko. Sisebenzisa ne-bioinformatics.

Sinazo zonke izixhobo apha. Akukho mntu umele [00:24:00] asixelele ukuba senze loo nto. Siyayenza loo nto. Nangona kunjalo, xa ufikelela ekwaluphaleni, xa ufuna ukujonga ukwakheka kwemithambo yegazi, ukudibana kwamajoni omzimba avuthiweyo, i-neuroimmunology, ngoko ke ukuba ufuna ukuba nokusebenzisana kwamalungu omzimba angaphandle kwengqondo, ukuba unendlela yokuziphatha kunye nomsebenzi, iisekethe ezintsonkothileyo, ukuqonda, sele sithethe ngaloo nto.

Umqobo wegazi-ubuchopho njengengcali yezonyango, i-pharmacokinetics, ukusebenzisana kwamathumbu-ubuchopho, okanye ufuna ukuvavanya isixhobo esitsha sotyando njengokuvuselela ubuchopho obunzulu, usadinga isidalwa esipheleleyo. Yiyo loo nto kusafuneka sifunde. Kodwa sonke sizama ukufumana ulwazi oluthe kratya sisebenzisa yonke into ekhoyo ukuze sithathe indawo, akunjalo?

Kwaye mhlawumbi kude kakhulu kwixesha elizayo, siya kuba nomzekelo ofanelekileyo oyiwele ledijithali lesigulana sethu kwaye onikwe lonke ulwazi malunga nesifo kunye nebhayoloji ukuqikelela imiba yokhuseleko kunye nokusebenza kakuhle. Kodwa asikude kangako kuloo nto kuba asinalo ulwazi esinokuluseta inkqubo [00:25:00].

Asazi ngokwaneleyo ngesi sifo kunye nebhayoloji. Yiyo loo nto kusafuneka senze uphando oluthe kratya kuba izigulane, zifuna ngokukhawuleza ukuphuculwa konyango.

UProfesa Tiago Outeiro: Kuhle kakhulu. Hayi, ndiyavuma ngokupheleleyo.

Ndicinga ukuba oku bekunolwazi kakhulu. Ngelishwa, sifikelele esiphelweni, ngoko ke ndingathanda ukunika ngamnye wenu ithuba lokongeza nantoni na enicinga ukuba siyiphosileyo eningathanda ukuyongeza. Jeff. 

UNjingalwazi uJeffrey Kordower: Ndifuna nje abantu abaqhelekileyo bazi ukuba sisebenza nzima kangangoko sinako, ngokukhawuleza kangangoko sinako, ukuzama ukunceda abantu abanesifo sikaParkinson kunye nezinye izifo eziwohlokayo. Iimodeli zezilwanyana zibalulekile kuloo nkqubo.

UProf. Tiago Outeiro: Franziska

UNjingalwazi uFranziska Richter Assêncio,: Kunjalo kanye. Kwaye senza konke okusemandleni ethu ukunciphisa, ukuphucula, ukutshintsha, kunye nokuba nedatha esemgangathweni ophezulu. Yiloo nto endingayongeza ecaleni lam.

UNjingalwazi Tiago Outeiro: Kuhle kakhulu. [00:26:00] Enkosi kakhulu, nobabini, ngexesha lenu, ngokuqonda intsimi enzima kangaka. Nisixelele ukuba sineemodeli ezininzi ezifumanekayo, ukusuka kwiimodeli zetyhefu ukuya kwiimodeli zemfuza ukuya kwiimodeli ezilawulwa yivektha yentsholongwane ukuya kwiimodeli ezisekelwe kwi-injection yeproteni.

Sijonge phambili kule njongo yokuba neemodeli zezifo ezininzi esicinga ukuba ziya kuba ngcono kakhulu ekuboniseni okwenzekayo ngokwenene kwingqondo yomntu osele ekhulile. Ngoko ke ndicinga ukuba kukho okuninzi onokuba nethemba ngako kwixesha elizayo. Kwaye ingcinga yokugqibela endifuna ukuyishiya kukuba ukusetyenziswa kweemodeli zezilwanyana sele kuchaphazele kakhulu kwaye kwatshintsha indlela esiphatha ngayo iParkinson's namhlanje, kwaye kuya kuqhubeka kunceda kwixesha elizayo.

Kwaye oko akuthethi ukuba, njengoko uFranziska watshoyo, asisebenzisi iimodeli zeeseli kunye nee-organoids nazo zonke ezi teknoloji zintle, kodwa kukho indawo [00:27:00] yazo zonke ezi modeli. Ngoko ke enkosi kakhulu kwakhona. Bekumnandi ukuba nawe kwi-podcast.

UProf. Franziska Richter Assêncio,: Enkosi, Tiago

UProfesa Jeffrey Kordower: Enkosi.

UNjingalwazi Tiago Outeiro: Kwaye enkosi kubo bonke abaphulaphuli bethu. Siyanimema ukuba niphinde nijoyine ii-podcasts zethu ezizayo.

Enkosi.