Kugadzirisa mhinduro yemuviri yekudzivirira muviri: LRRK2 uye GBA1 mutations

Muchidzidzo ichi, vanyori vanoongorora kuti maviri emhando dzakakosha dzemajini echirwere cheParkinson anokanganisa sei kupindura kwemuviri kumuenzaniso webhakitiriya zvichiratidza hukama huripo pakati pemajini, nharaunda, uye kuzvimba muParkinson. Nhasi, ndinofara zvikuru kuti ndabatanidzwa nemumwe wevanyori vanoenderana nepepa iri, Rebecca Wallings, muongorori kubva kuIndiana University kuIndianapolis.

Becky, tinokugamuchirai kupodcast.

Dr. Rebecca Wallings: Ndatenda zvikuru nekundigamuchira, Michele.

Dr. Michele Matarazzo: Saka ndinoda kutanga kubva pamifananidzo mikuru. Iyi inyaya yakaoma. [00:01:00] Ndinofunga kuti tava kutanga kunzwisisa zvishoma nezvezvinhu izvi uye nezvekubatana pakati pekuora kwetsinga, kuzvimba, mhinduro yemuviri, zvinhu zvakadai. Uye kwave nekufarira kuri kukura kwebasa remuviri wemuviri muchirwere cheParkinson mumakore apfuura.

Chidzidzo chenyu chave pakati pekusangana kwemajini neimmunology. Mungatiudze here kuti chii chakakukurudzirai kuti muongorore kuti LRRK2 neGBA1 mutation zvinokanganisa sei kupindura kwemuviri? Uye kunyanya kana mukasangana nechinhu chekunze, bhakitiriya munyaya iyi?

Dr. Rebecca Wallings: Ehe, zvechokwadi. Ndichatanga nechikonzero nei LRRK2 neGBA, saka kune vateereri vangave vasingazive nezvezvinhu zviviri izvi zvine njodzi yemajini zvine chekuita nechirwere cheParkinson. Takasarudza kutarisa LRRK2 neGBA, nekuti LRRK2 ndiyo inonyanya kupararira mumhuri ine chekuita nechirwere cheParkinson uye GBA ndiyo inonyanya kupararira mumajini ine njodzi yemajini ine chekuita neParkinson.

Uye chikonzero chataida kutarisa izvi zviviri [00:02:00] kukanganiswa kwemajini panguva imwe chete ndechekuti kune kushanda kwakawanda pakati pemapuroteni maviri aanogadzirisa. Uye anoita seanosangana zvakanyanya muimmune system, LRRK2 neprotein inogadziriswa neGBA, GCase. Inowanikwa zvakanyanya muimmune system, kunyanya masero e myeloid.

Uye vane basa guru mu lysosomal biology, uye tinoziva kuti LRRK2 neGBA zvinogadzirisa mashandiro e lysosomal uye kushanduka kwavo kunogona kukanganisa mashandiro e lysosomal mu neurons, asiwo mumamiriro emasero ekudzivirira muviri mukati nekunze kweuropi.

Semurabhoritari, chinyorwa ichi chakanyanya kuitwa ndichiri postdoc naMalú Tansey. Kubva ipapo ndakatanga rabhoritari yangu uye iye zvino ndiye mushandi pamwe chete neni izvo zvinonakidza zvikuru. Taifarira zvikuru basa re peripheral immune system muchirwere cheParkinson sezvo chave chichioneka zvakanyanya mumakore makumi maviri apfuura, ndingati, izvozvo hazvisi chete kuti kuzvimba kweuropi ndiko kunokonzera chirwere cheParkinson nekuti hachisi kungokonzerwa nerufu rwetsinga dzeropa nekugadzirwa kwetsinga dzeropa, asi chiri kutobatsirawo pachirwere ichi.

Asi kuzvimba uku hakusi kwechikamu chepakati chetsinga. Tinoona kuzvimba kwemuviri muvarwere muzvirongwa zvedu zve preclinical. Uye data rekare ratakaunganidza tisati tanyora, tichibatsirana neYunivhesiti yeSydney murabhoritari yaNicolas Dzamko, takaona kuti maPBMC evarwere ane maLRRK2 aya kana aya maGBA1 mutations aive nemhinduro dzakasiyana dzekukurudzira maererano nemhinduro dzavo dzekudzivirira muviri uye lysosomal biology yavo.

Asi mudata rekutanga iroro taitarisa pamwe mhinduro shoma yemuviri yekudzivirira chirwere nekuti taitora maPBMC aya kubva kuvarwere, tichiaisa mupurasitiki, uye tichiarapa nema cytokines akasiyana-siyana. Iyi inzira yakanaka yekukurudzira nekukurudzira immune system.

Asi taida kuchinjira kune zvimwe zvinosimudzira immune system [00:04:00] zvine chekuita nemuviri mupfungwa yekuti taida mabhakitiriya chaiwo, mavhairasi chaiwo, uye kunzwisisa kuti masero ekudzivirira immune system anopindura sei kune izvi. Nekuti tinotenda kuti chirwere cheParkinson chine gene nenharaunda maererano nekukura kwenjodzi.

Saka tinoda kuti munzwisise kuti kushanduka kwemajini uku kunokanganisa sei mashandiro emuviri kuzvirwere zvepasi rose izvo vanhu vangasangana nazvo zuva nezuva. Saka sei pseudomonas aeruginosa kunyanya? Kune avo vangave vasingazive kuti aeruginosa chii, mabhakitiriya anowanikwa zvakanyanya muvhu nemumvura.

Ndiyowo nzvimbo huru yezvirwere zvinotapukira vanhu muzvipatara zvakare. Hapana ruzivo rwezvirwere zvinobatanidza chirwere cheParkinson nebhakitiriya iri nekuti kana ukanyanya kusangana naro, ndipo panonyanya kuva panjodzi yekuwana chirwere cheParkinson. Asi ruzivo kubva mumarabhoritari edu mumakore mashoma apfuura, takaona kuti, kunyanya nekuchinja kweLRRK2, kana ukaratidza [00:05:00] pseudomonas aeruginosa kuti LRRK2 igumburwe mumuenzaniso wembeva wechirwere cheParkinson, nzira iyo mbeva idzi nemasoja avo ekudzivirira muviri anobata nayo bhakitiriya iyi zvakasiyana zvikuru nenzira iyo ndinoti mbeva yemusango nhema nhanhatu ingapindura nayo bhakitiriya iyi. Saka taida kunzwisisa, zvakanaka, tinozvionawo here izvi muvarwere?

Dr. Michele Matarazzo: Wow. Saka irworwo ruzivo rwakawanda. Saka zvinonakidza chaizvo nekuti wanga uchishanda murabhoritari yako uye rabhoritari yaDr. Tansey yanga ichishanda pakudzivirira muviri nekupa danho iri kwete kungotarisa kuzvimba chete, asi kuti masero ekudzivirira muviri anopindura sei padambudziko, dambudziko rekunze, uye dambudziko rekunze riripo munyika yedu chaiyo yekunze. Handiti? Saka ndinofunga kuti ndiyo nzira inonakidza kwazvo. Uye ikozvino nditaure nezvekwakabva. Ngatienderere mberi ngatienderere kuongororo pachayo. Ngatitaure nezve dhizaini. Saka wakabatanidza varwere vane LRRK2 mutations vane GBA1 mutation, idiopathic [00:06:00] PD, vanodzora hutano.

Tisati tapinda mumhinduro, mungatsanangura muchidimbu kuti mapoka aya akasarudzwa sei uye kuti chii chawaida kuenzanisa pakati pavo?

Dr. Rebecca Wallings: Ehe, kwete, zvechokwadi. Saka zviri pachena kuti vanhu ava vakazvipira kupa maPBMC avo muchidzidzo ichi vakaenzana zera nebonde. Nekuti tinoziva kuti kune mhinduro dzakasiyana dzemuviri pazera rakasiyana uye dzakasiyana pakati pevarume nevakadzi zvakare. MaPBMC aya akawanikwa neMichael J. Fox Foundation pamwe chete naRoy Alcalay paYunivhesiti yeColumbia pamwe neTel Aviv. Uye Alicia Garrido, ari kuchipatara chekiriniki cheBarcelona. Vanhu ava vakawanikwa zvakanyanya nekuda kwekuvapo kweLRRK2 mutation kana GBA mutation kana vanhu vane chirwere cheParkinson vasina mutation inozivikanwa.

Zvimwe zvinodiwa zvekubvisa vanhu vaisanganisira vanhu vaiva nezvirwere zve autoimmune nekuti zviri pachena kuti izvozvo zvaizova dambudziko guru kune rudzi rwekudzidza kwedu. Uye isu [00:07:00] taifanirawo kubvisa vanhu vaitora mishonga yekudzivirira kuzvimba. Chero chii zvacho chaizogadzirisa immune system taifanira kuvabvisa nekuti zviri pachena kuti zvaizova dambudziko guru uye zvinotadzisa kugona kwedu kutsanangura data redu. Pepa iri mhedzisiro yekushanda kwemakore matanhatu tichibatsirana nenyanzvi dzakasiyana siyana dzepfungwa tichipa varwere PBMCs uye isu tichishanda pamwe chete naNicolas Dzamko paYunivhesiti yeSydney, uko kuburikidza nezvikamu zvakasiyana zvepurojekiti iyi takanga tichigadzirisa nzira yekubvisa PBMCs idzi, kudzichengetedza uye dzozokwanisa kutumirwa kungave kwataive paYunivhesiti yeFlorida apo bepa iri raiitwa kana kuYunivhesiti yeSydney kuitira kuti tigone kudzoreredza PBMCs idzi uye tobva taita bvunzo dze ex vivo padziri. Izvo zvave, ndinofunga sedanho rekuderedza mwero webasa kwenguva yakareba. MaPBMC [00:08:00] haawanzo vhara zvakanaka, dzimwe nguva haunyatso chengetedza zvakanaka. Taifanira kugadzirisa nzira iyi kuitira kuti tiwane goho rakakura uye PBMCs dzirambe dzichirarama. Uye izvozvo pachazvo zvakatora makore maviri kuti zviitwe nemazvo uye tive nechokwadi chekuti taigona kumhanyisa bvunzo idzi panguva imwe chete mumasangano maviri akasiyana uye tive nechokwadi chekuti taigona kuona ma phenotype akafanana, takakwanisa kudzokorora zvakawanikwa nemumwe nemumwe. Saka bepa iri raive basa rerudo.

Dr. Michele Matarazzo: Ehe. Zvino, usati wapinda muongororo, waitarisira chii? Uye pamwe mubvunzo ndewokuti, waitarisira here kuva nemigumisiro yakafanana pakati peLRRK2 neGBA kana chero musiyano wawaimbofunga kuti ungave uripo.

Dr. Rebecca Wallings: Mubvunzo wakanaka chaizvo. Panyaya yePBMC idzi, takadziisa mupurasitiki uye takadzishandisa vehicle kana pseudomonas aeruginosa. Asi takazoshandisawo pamwe chete nemamwe macompounds anotarisa ku. LRRK2 kinase domain kana imwe compound inozivikanwa ne [00:09:00] kuwedzera basa reGCase.

Nekuti nekuchinja uku kweGBA, une kudzikira kwekushanda kweGCase enzyme iyo GBA gene inoisa. Saka kana tichitarisa kurapwa uku kwakasiyana, chero hunhu hwatinoona, taifunga kuti kurapwa uku kwaizonyatsoita kuti kuve kwakanaka. Uye zvataitarisira kuona zvakataurwa mumapepa apfuura neboka raMatt Lavoie richiri kuYunivhesiti yeFlorida, serimwe remapoka akashuma izvi, zvinoratidza kuti kuchinja kweLRRK2 kunogona kugadzirisa mashandiro eGCase.

Saka vanhu vasina GBA1 mutations asi vane LRRK2 mutation zvinoita sekunge pane shanduko yeGCase activity muvanhu ava. Saka zvechokwadi pane imwe mhando yekubatana uye rudzi rwekutaurirana pakati pemapuroteni maviri aya kunyanya pa lysosome. Saka taitarisira zvizere kuti kurapwa kwemishonga iyi kwaizovandudza phenotypes mumapoka akasiyana evarwere zvakare.

Dr. Michele Matarazzo: Uye tisati tanyatsonzwisisa mhedzisiro yacho, ndiri kuramba ndichitarisa nzira dziri pano nekuti dzinonakidza zvikuru. Chimwe chezvinhu [00:10:00] chandakaona ndechekuti LRRK2 yese yaive mutation imwechete, G2019S, nepo muGBA1 maive nemhando dzakasiyana dzemutation.

Unofunga kuti izvi zvinoreva here kuti pane musiyano nekuti shanduko dzakasiyana hadzidzivise basa reGCase padanho rimwe chete?

Dr. Rebecca Wallings: Ehe. Wasvika padanho repamusoro. Zvechokwadi. Saka sezvawataura, nekuchinja kweLRRK2 takakwanisa kuva nekutakura kwese kweG2019S. Ndiyo shanduko yakajairika kupfuura dzose dzekuchinja kweLRRK2. Saka zvaive nemusoro kuti tikwanise kuva neG2019S yakawanda. Zvinosuwisa kuti kana uchishanda nevarwere, unofanirwa kushanda nezvaunazvo.

Uye zvingadai zvakanaka kudai taigona kupatsanura varwere veGBA zvichienderana nekuchinja kwavo kweGBA. Nekuti une chokwadi, kuchinja uku kweGBA kunoderedza kushanda kweGCase nematanho akasiyana. Uye takaona kusiyana kwakawanda muvarwere vedu veGBA, uye tinofunga kuti kunokonzerwa zvakanyanya nekuda kwekuchinja kwavo kweGBA.

Asi zvinosuwisa kuti nekuguma kwatakaita varwere ava, takanga tisina simba rakakwana rekuisa muzvikamu [00:11:00] pakuchinja kwemuviri. Ongororo iri kuenderera mberi iri kutarisa izvozvo nekuti tinoda kunzwisisa chinangwa chikuru chedu uye Malu's Lab iri kuedza kunzwisisa kuti mhinduro dzakasiyana dzemuviri dzinogona sei kubatsira mukusiyana kwatinoona muchirwere cheParkinson, mupfungwa iyi yekiriniki, mupfungwa yezvirwere zvakare.

Saka tinoda kunzwisisa zviri kuitwa nekuchinja uku kwakasiyana-siyana nekuti tinotenda kuti pachava nemhinduro dzakasiyana, kunyanya muimmune system zvechokwadi.

Dr. Michele Matarazzo: Zvakanaka. Tinotarisira zvimwe zvidzidzo zvakaburitswa nemi neboka renyu. Zvino, ngatiendei kumhedzisiro yeiyi. Chii chakaitika pamakatarisa GBA1 mutation uye mhinduro yemuviri?

Dr. Rebecca Wallings: Ndichaedza kupfupikisa zvinhu zvinokosha. Nekuti ndine chokwadi chekuti sezvamakadzidza bepa iri, pane zvakawanda zvakawanikwa. Tine mapoka akasiyana-siyana, marapirwo akasiyana-siyana, marudzi akasiyana-siyana emasero emuviri. Tiri kutarisa kuverenga kwakasiyana-siyana. Ipepa rine mhedzisiro yakawanda, saka ndicharichengeta kusvika kune zvakakosha.

Chimwe chezvinhu zvatakawana chaive chimwe chezvinhu zvisingashamisi zvakanyanya [00:12:00] kunyanya GBA Parkinson's PBMCs, patakavarapa nepseudomonas aeruginosa, vakanga vawedzera kuburitsa ma cytokines mumasero. Saka vaiva nekuwedzera kwekuzvimba kupseudomonas aeruginosa.

Izvozvo hazvina kushamisa zvakanyanya zvatakaona nekuti kune mabhuku akawanda anoratidza kuti kune kuwedzera kwemhinduro yekuzvimba muchirwere cheParkinson. Kune kuwedzera kwekuzvimba. Zvinogona kunge zvichikonzera kuzvimba kweuropi uye kuora kwetsinga kwatinoona muuropi.

Saka izvozvo hazvina kushamisa zvakanyanya. Chakanyanya kushamisa ndechekuti hatina kuona maitiro akawanda ekubvisa ma cytokines muvarwere veLRRK2. Kutaura zvazviri, mune mamwe ma cytokines, saka neTNF neIO 10, kwaive nekudzikira kwemhinduro iyo maLRRK2 aiburitsa nema cytokines avo. Izvo, pamwe ndichataura nezvazvo mushure mezvo kana ukabvunza nezvemhedzisiro yeizvi [00:13:00]. Saka zvinoita sekunge LRRK2 neGBA zvaipindura zvakasiyana, izvo pachazvo zvaishamisa tichifunga kuti tinoziva kuti LRRK2 neGBA zvinosangana munzira dzakafanana asi zvinoita sekunge hazvisi kupindura nenzira imwecheteyo, kunyanya ku pseudomonas aeruginosa.

Saka izvozvo pachazvo zvainakidza zvikuru. Chimwe chaive mhedzisiro isingashamisi ndechekuti mushonga wataishandisa kuwedzera basa reGCase hauna kuita zvakawanda kuvarwere veGBA. Takaona mhinduro idzi dzakachinja dzecytokine. Takaona mamwe maGBA dependent phospho RAB10 akachinja anova aa kinase substrate yeLRRK2.

Saka zvinoita sekunge GBA iri kuchinja mashandiro eLRRK2 mune aya masero ekudzivirira muviri. Asi patakaarova neGCase activator, hatina kuona mhinduro yakawanda kudaro. Uye chimwe chezvinhu zvatinokurukura nezvekuti nei izvi zvingave zvichiitika ndechekuti panogona kunge paine mhinduro ye [00:14:00] kubva kune mamwe ma enzymes e lysosomal kurwisa chokwadi chekuti kune lysosomal dysfunction inokonzerwa nebasa iri reGCase, uye nekushandisa GCase, unenge wava kuda kusvika padanho repamusoro. Kuti lysosome yatotanga kutsiva uye kuramba ichifara. Saka kuvapo kweGCase activator iyi hakunyatsoita zvakawanda.

Chainyanya kufadza ndechekuti patakatora LRRK2 mutation, LRRK2 mutant PBMCs, uye takavarapa neGCase activator, takaona mhinduro dzakasiyana-siyana. Takaona kuwedzera kweMHC2 expression paplasma membrane yemhando dzakasiyana dze monocyte.

Uye kune vateereri vangave vasingazive nezveMHC2 ijini rembeva, asi HLA-DR muvanhu. Iro gene remaantigen rinowanikwa pamasero emaantigen. Uye takaona kuwedzera kweizvi patakarapa maPBMC eLRRK2 mutant carrier neGCase activator iyi.

Uye tinotaura [00:15:00] nezvechikonzero nei izvozvo zvingave zvichiitika, nekuda kwekuti kune lysosomal dysfunction muvarwere veLRRK2, kuvapo kwerudzi urwu rweGCase activator kunotanga system iyoyo uye kunobvumira aya maantigen akasiyana ari kugadziriswa mulysosome ayo anozobva aendeswa kuplasma membrane kuti aendeswe kumasero eT.

Isu tinofunga kuti rudzi irworwo rwekupinza muhurongwa ihwohwo. Saka chokwadi chekuti takakwanisa kuona izvozvo muLRRK2, asi GBA yakapotsa yava nemhedzisiro iyi yatisina kukwanisa kuona, chaive chinonakidza chaizvo. 'nekuti zvinoratidza kuti pane kutaurirana kwakaoma pakati pemapuroteni maviri aya uye kunyanya kana akachinja, izvo zvinoda kunyatso patsanurwa kuti unzwisise paari kutaura uye nei kurova LRRK2 neGCase activators kuchiita chimwe chinhu, asi hazviiti izvozvo kune GBA mutations dzine GCase shoma.

Zvaive zvisinganzwisisike uye tichiri kuzvifunga.

Dr. Michele Matarazzo: Ehe. Ndinofunga izvi zvinovhura mukana wekufunga mazano matsva uye kutsvaga pfungwa itsva ichazotanga mapurojekiti matsva. Uye chaizvoizvo wave uchitsanangura zvakajeka kuti GBA neLRRK2 ndeapi majini anonyanya kuenderana nechirwere cheParkinson, asi kubva pakuona kwekiriniki, padanho remunhu oga haasiyaniswi neParkinson's idiopathic. Asi padanho reboka, ane mutsauko. Uye semuenzaniso, tinoziva kuti GBA ine phenotype yakasiyana isiri yemotor. Kana iri LRRK2, zvakasiyana nemaonero asiri emotor, inowanzoita zviri nani.

Saka unofunga here kuti musiyano uyu waunoona kubva pamaonero ekudzivirira muviri nekuzvimba une chekuita ne phenotype, kune rumwe rutivi? Uye zvakare hazvisi chete kuti zvakasiyana nemaonero e phenomenological, asi zvakasiyanawo kana ukatarisa vanhu vane uropi vane LRRK2, semuenzaniso, vanowanzova nehuwandu hushoma kana hushoma hwe alpha synuclein aggregation zvichienzaniswa ne idiopathic PD kana ku GBA-PD, uko synuclein inofanirwa kunge iri iyo huru [00:17:00] protein aggregated uye kana ukatarisa data razvino ne alpha synuclein seeding assay uchatove nehuwandu hwakanyanya kupfuura idiopathic Parkinson's disease nevanhu vakachinja GBA. Saka unofunga kuti pathological uye phenomenology zvine chekuita pano nezvatinoona mu immune response.

Dr. Rebecca Wallings: Zvechokwadi. Zviri pachena kuti izvozvi, zvese zvandiri kuda kutaura ifungidziro. Zviri pachena kuti ndezvekufungidzira. Saka rimwe bepa iro, munyori wekutanga webepa iri aive Dr. Julian Mark, uyo panguva iyoyo aive mudzidzi weMD PhD muMalu's Lab wandakava nerukudzo rwekutarisira sezvo ndaiva postdoc naye.

Aiva nerimwe bepa rakabuda nguva pfupi yapfuura bepa iri. Hatina kana shanduko dzeLRRK2 kana GBA mubepa iri. Taiva nevarwere veParkinson's vane idiopathic pamwe chete nevanhu vaiva neRBD. Saka REM behavioral sleep disorder semhando yeprodromal group. Uye zvakare kudzora hutano hwetsinga. Uye takaita imwe nzira yakafanana mukuyedza uku muna [00:18:00] kunyanya, takanga tisiri kushandisa bhakitiriya, taishandisa cytokines kukurudzira immune system.

Asi Julian akaita kuti vanhu vaiva neParkinson's vapatsanurwe, akavapatsanura zvichienderana nekuti vaiva neParkinson's pakutanga here. Saka vakaonekwa kuti vane chirwere ichi mumakore mashanu apfuura, kana kuti vaiva nechirwere chataiti chirwere cheParkinson's chiri pakati nepakati. Saka vakanga vaine Parkinson's kwemakore anopfuura gumi.

Saka vaive padanho rakasiyana rekufambira mberi kwekiriniki. Uye chaakawana ndechekuti, pamwe nemaitiro ayo masero emuviri aya aiburitsa ma cytokines, paive nehukama hwakanaka pakati pehuwandu hwema cytokines aigadzirwa nevanhu ava neUPDRS scores.

Saka zvaiita sekunge kusashanda zvakanaka kwemasoja emuviri kwaivapo, zviratidzo zvemuviri zvairatidza vanhu ava. Uye izvozvo zvinokonzerwa nekusiyana kwemasoja emuviri pachawo here, kana kuti imhaka yekuti vane mazera akasiyana zvishoma. 'nekuti zviri pachena kuti vanhu vaiva nechirwere cheParkinson's [00:19:00] vaiva vakuru zvishoma, zviri pachena kuti ndivo vaiva nechirwere cheParkinson's pakutanga.

Zvaive chibereko chekufambira mberi kwemuviri uye kugadzirwa kwetsinga dzeropa uye kuwedzera kwekufambira mberi kwechirwere kwakadzokera kumasoja emuviri here? Hatisati tava nechokwadi zvachose, asi zvinoita sekunge shanduko mumhinduro yemasoja emuviri dzine hukama nemaitiro aya ekiriniki atinoona. Uye tinofunga kuti izvi zvichaitikawo patinotarisa shanduko dzakasiyana dzevarwere.

Saka kana tiine vanhu vane GBA, LRRK2 mutations, tinotarisira kuti tichaona mhinduro dzakasiyana dzemuviri zvichienderana nemamiriro emajini, mamiriro echirwere. Uye rimwe remapurojekiti atichatanga mumwedzi mishoma inotevera murabhoritari yangu nderekuti tiri kuedza kunzwisisa kuti zviratidzo zvemuviri wekudzivirira muviri wekukwegura, immune system yekukwegura zvinonzwika sei senzira isina kujairika yekutsanangura, asi chaizvoizvo tinofarira zvikuru kusasimba kwemuviri uye kupera simba kwemasero emuviri uye pfungwa iyi yekuti [00:20:00] kune mhinduro yemuviri yakadzvinyirirwa inoitika mune vamwe varwere. Uye tichatarisa aya ma phenotypes mukuchinja kwakasiyana kweLRRK2, GBA mutations, idiopathic Parkinson's disease, varume nevakadzi, kuti tiedze kunzwisisa kuti aya ma phenotypes akasiyana emuviri wekudzivirira muviri anoenderana sei nekufambira mberi kwekiriniki uye pathological pamwe nekunzwisisa kuti anobatsira sei kune kusiyana uku.

Dr. Michele Matarazzo: Zvakanaka, basa rakawanda riri kuitwa. Zvino chimwe chezvinhu chaunoratidza ndechekuti mhedzisiro yekuchinja kwemajini inoumbawo maitiro anoita masoja emuviri kuchirwere chinotapukira. Unofunga kuti izvi zvinotiudzei nezvebasa rehutachiona kana kusangana nezvirwere munharaunda yeParkinson's?

Dr. Rebecca Wallings: Ndinofunga zvinoratidza kuti pane kudyidzana kwemajini nenzvimbo, kunyanya kana zvasvika kumasoja emuviri ekudzivirira chirwere cheParkinson. Ndinofunga kuti LRRK2 muenzaniso wakanaka kwazvo wekusimbisa pfungwa iyoyo yatinoziva kuti shanduko dzeLRRK2 hadzipindi zvachose.

Uye tinoziva kuti shanduko dzeLRRK2 [00:21:00] dzinobatanidzwawo nezvirwere zvakasiyana-siyana nezvimwe zvirwere zvine chekuita nekuzvimba zvakaita sechirwere cheCrohn nechirwere cheulcerative colitis. Zvakanyatso dzidziswa munyaya yeTB. Tinoziva kuti LRRK2 ine basa rekuita kuti dziviriro yemuviri ishande uye mhinduro kuzvirwere zvakasiyana-siyana. Uye ndinofunga kuti pacharo pane humbowo hwakawanda hunoratidza kuti kune basa rezvirwere uye mhando idzi dzezvirwere zvinokonzera kuzvimba munzvimbo muchirwere cheParkinson.

Asiwo, ndinofunga kuti kana tikangotarisa data rezvirwere, senge furuwenza yeSpain semuenzaniso, patinoona kuti panguva iyoyo zvaiitika paive nekuwedzera kukuru kwevanhu vakaonekwa vaine chirwere cheParkinson mumakore akatevera, zvichiratidza kuti kusangana nezvirwere zvisingaperi uye kuzvimba kwenguva refu kunowanzoita kuti vanhu vari panjodzi, vangangove majini echirwere cheParkinson, vabve vayambuka mukana iwoyo kuti vabate chirwere cheParkinson vowana kuongororwa kwekiriniki.

Dr. Michele Matarazzo: [00:22:00] Zvakanaka. Zvino, ndichitarisira mberi, watoburitsa pachena mamwe emapurojekiti auri kushanda paari mune ramangwana. Ungati mubvunzo upi unotevera unofanira kupindurwa mushure mebasa iri?

Dr. Rebecca Wallings: Kwete, zvechokwadi. Chimwe chezvinhu zvinonyanya kutariswa nerabhoritari yangu nerabhoritari yaMalu ndechekuti tinonanga sei masoja emuviri uye, zvakare, kuti ndiani, uye riini. Ndakataura nezveimwe yemapepa aJulian kwatakaongorora vanhu vane RBD uye takavaenzanisa nevanhu vane chirwere cheParkinson's chiri kutanga kana kuti chiri pakati nepakati.

Uye zvatakaona zvainakidza zvikuru uye zvakachinja chaizvo maonero angu ekuzvimba muchirwere cheParkinson. Zvatakawana ndezvekuti vanhu vane RBD vaiva nerudzi urwu rwe hyper inflammatory immune response kune akasiyana immune activators. Asi pawakatanga kubva paRBD wobva watanga kutarisa Parkinson's yekutanga uye pakati nepakati Parkinson's uye PBMC's immune responses yavo, zvakada kuita seizvi [00:23:00] hyperactivation ichiteverwa nekudzvinyirirwa uku kunotevera nenzira iyi apo une activation yakakura ye immune system muRBD.

Asi paunotanga neRBD uchienda kuParkinson's yekutanga uchienda kuParkinson's iri pakati nepakati, unowedzera kudzvinyirirwa. Uye izvozvo zvaishamisa nekuti tinofunga kuti vazhinji vanoona kuzvimba sechinhu chinokanganisa muviri zvakanyanya. Kunowedzera. Chinhu chinofanira kudzvinyirirwa.

Zvinofanira kubviswa. Ndosaka mishonga yakawanda yekurapa yakasvika padanho rechipiri yekuedza kwekiriniki yakashandisa nzira iyi yekudzvinyirira, yekudzivirira kuzvimba. Asi hapana kana imwe yemiedzo iyoyo yekiriniki yakapa mhedzisiro inovimbisa. Ini ndinofunga, uye fungidziro yangu yerabhoritari yangu yese ndeyekuti tanga tichitarisa kuzvimba nenzira isiriyo. Zvinoita sekuti mumakore ekutanga echirwere cheParkinson, hongu kune kuzvimba kwenguva refu kuri kuitika. Pane mhinduro dzekudzivirira dziviriro dzakanyanya. Asi chimwe chinhu chinoitika [00:24:00] mumuviri wemunhu, mukutarisana nekuzvimba kwenguva refu. Asi kana ukabatanidza izvozvo nesystem yekudzivirira muviri inokwegura, iyo inowanzo deredzwa sezvatinokura.

Sisitimu yekudzivirira muviri inochinja-chinja. Inogara ichiedza kugadzirisa maitiro ayo kuitira kuti isakuvadze mudziviriri. 'nekuti ndicho chinhu chikuru chayo, ndechekuti inoda kuchengetedza mudziviriri, handiti? Saka kana ikabatwa nekuzvimba uku kusingaperi, pane kuwedzera uku kwekushanda kwemakore nemakore, nekufamba kwenguva immune system ichachinja uye ichatsiva nekudzvanya pachayo.

Uye ongororo yangu yakawanda ichinyorwa chakanyorwa naMalu chandiri kushanda nacho murabhoritari yangu chinoratidza kuti panogona kunge paine kudzvinyirirwa kwemasoja emuviri muvanhu vane chirwere cheParkinson, izvo, pandinotaura izvozvo, vamwe vanhu vanonditarisa zvishoma vachindiseka voti, unorevei?

Izvi hazvisirizvo zvave zvichitaurwa nenyanzvi kwemakore gumi kusvika makumi maviri apfuura, asi zvinoita sekunge vanhu vane chirwere cheParkinson's havakwanise kugadzirisa kuzvimba, iro ndiro dambudziko. Zvinoita sekunge kune kuzvimba kusingarapiki pakutanga uko kunogara kuripo [00:25:00], asi kana ukavabata nehutachiona, kumutsa cytokine, chero dambudziko rekudzivirira muviri, zvinoita sekunge pane kutadza kupindura nekugadzirisa kuzvimba kunotevera, zvinoreva kuti kuzvimba kusingarapiki kunoramba kuripo. Kwenguva yakareba. Saka pachinzvimbo chekuedza kudzvinyirira immune system inogona kunge yakadzvinyirirwa, maitiro erabhoritari yangu uye tiri kuedza kunzwisisa kana iyi iri nzira yekurapa yekuitarisa muParkinson's, asi tinoda chaizvo, handisi kuzoti kumutsa immune system, asi kuvandudza immune system.

Edza kuidzosera kumamiriro ayo ehomeostasis uko inokwanisa kupindura matambudziko ekudzivirira muviri nenzira yayaimboita payaiva mudiki, ndinofunga ndiro izwi rekutsanangura.

Dr. Michele Matarazzo: Saka pachinzvimbo chekushandisa chikamu ichocho chehyper inflammation senzira yekuchidzikisa, dzivisa kuchidzikisa gare gare.

Dr. Rebecca Wallings: Ehe. Saka apa ndipo panotanga kutaurwa kuti, [00:26:00] tinozvinanga riini uye tinozvinanga sei. Saka nzira iyo, uye iyi inzira yakapfava yekutsanangura, asi nzira yandinofunga nezvayo mumusoro mangu ndeyekuti tiri kufunga nezvekutarisa masoja emuviri muvanhu vari panjodzi yeParkinson's, saka matanho eprodromal apo pane hyperactivation iri kukonzera kuzvimba uku kusingaperi.

Muvanhu ivavo, zvine musoro kuedza kudzvinyirira masoja emuviri nekuti tinoda kubvisa kuzvimba ikoko kusingaperi. Asi zvinoita sekunge muongororo yangu, parizvino ongororo yangu yakawanda yave iri pakuchinja kweLRRK2. Saka kunyangwe izvi zvine chekuita nedzimwe shanduko dzemajini kana chirwere cheParkinson chisinganzwisisike kana kuti chinongoerekana chaitika, hatisati tava nechokwadi.

Asi zvinoita sekunge nekuchinja kweLRRK2 kwatave tichidzidza murabhoritari yangu, zvinoita sekunge kana chirwere cheParkinson chatanga uye paine zviratidzo zvekiriniki uye vawana chirwere ichocho, zvinoita sekunge masoja emuviri ane rudzi urwu rwekudzvinyirira.

Saka zvingangoitika, kuedza kushandisa mushonga uyu unodzvinyirira [00:27:00] wekudzivirira kuzvimba nevanhu ivavo hazvingakodzeri, zvingafanira kuedza imwe nzira yekurapa kuti muviri udzoke pakushanda zvakanaka nekuwedzera mashandiro acho. nekuti haudi kuwedzera mashandiro uye muviri wemuviri watove usina kushanda zvakanaka, tsigira.

Hezvo taenda. Ehe.

Dr. Michele Matarazzo: Zvakanaka. Becky, ndatenda zvikuru. Dai waifanira kusarudza meseji imwe chete yaunoda kuti chiremba kana muongorori anofarira chikamu ichi atore kubva mukudzidza kwako nebasa rako, ingava ipi iyoyo?

Dr. Rebecca Wallings: Ndinoda kuti vanhu vanzwisise kuti immune system yemuviri ndiyo inonyanya kukonzera chirwere cheParkinson. Saka ongororo dzakawanda dzatakaita dzinoratidza kuti kuzvimba kwemuviri muParkinson nezvimwe zvirwere zveneurogenerative ndiko kwakakosha pakukura kwechirwere ichi. Hazvisi kungozvimba kweuropi chete mukati meCNS, zviri kuitikawo kunze kweuropi, izvo zvandinofunga kuti zvinovhura nzira yakawanda yekurapa.

Sisitimu yekudzivirira muviri iri kunze kweuropi iri nyore kwazvo kuibata [00:28:00]. Pane kuedza kuibata nesisitimu yekudzivirira muviri iri muuropi. Saka kana tikakwanisa kunzwisisa kuti sisitimu yekudzivirira muviri iri kubatsira sei kuzvirwere izvi uye kuti tingazvibata sei kana tichitarisa chirwere ichi, ndinofunga kuti zvichavhura nzira dzakawanda dzekurapa dziri nyore kushandisa.

Dr. Michele Matarazzo: Zvakanaka, Becky, ndatenda zvikuru nekundibatana nhasi. Yaive hurukuro yakanaka kwazvo pamusoro penyaya ine chekuita nepfungwa iyi, isina kutaurwa zvakanaka uye isinganzwisiswe zvakanaka. Ndingati. 

Dr. Rebecca Wallings: Ndatenda zvikuru. Zvaive zvinofadza.

Dr. Michele Matarazzo: Zvakanaka, takambokurukura nezvepepa rinonzi Parkinson's Linked LRRK2 and GBA1 mutations rinogadzirisa mhinduro yekudzivirira muviri kuPseudomonas aeruginosa rakaburitswa paMovement Disorders Journal.

Saka ndinokukokai kuti muende kunoona uye ndinokutendai nekuteerera. [00:29:00] [00:30:00]