Gene da ke fitar da toxic tau daga neurons yana share shi amma kuma yana taimaka masa ya yadu

Rayuwa biyu ta motar da ke kai tau daga neuron zuwa neuron

A cutar Alzheimer’s, furotin tau ba ya tsaya a wuri guda. A cikin neuron mara lafiya, tsarin furotin ɗin yana lalacewa kuma yana taruwa ya zama tangles; daga nan, ta wata hanya, lalacewar tana bayyana a neuron na gaba, sannan na gaba, tana yaduwa cikin kwakwalwa a tsarin da ke tafiya tare da tabarbarewar ƙwaƙwalwa da tunani. Tsawon shekaru an san cewa tau yana yaduwa, amma mechanism ɗin bai fito fili ba: ta yaya tau yake fita daga sel ɗaya ya shiga wani?

Wani bincike a Cell ya bayar da wani muhimmin ɓangare na amsar, tare da abin mamaki. Abin da ke taimaka wa tau fita daga neurons shi ne Arc—gene da furotin ɗinsa ke nuna halaye masu kama da na wani tsohon virus fiye da na furotin na yau da kullum. Arc yana iya haɗuwa ya samar da capsids masu rami waɗanda ke ɗaukar kaya tsakanin sel na kwakwalwa. Masu binciken, ƙarƙashin jagorancin ƙungiyar Jason Shepherd a University of Utah, sun gano cewa Arc yana kama tau ya taimaka saka shi cikin extracellular vesicles, ƙananan kumfar membrane da neurons ke fitarwa. Idan babu Arc, yaduwar tau daga sel zuwa sel kusan tana tsaya.

Abin mamaki shi ne abin da ya hana Arc zama “mugun actor” mai sauƙin fahimta. Hanyar packing ɗin da ke yaɗa tau zuwa neurons maƙwabta tana kuma cire tau mai guba daga neuron da ke fitar da shi. Arc ba kawai mai lalata bane; kamar motar kai kaya ce wadda hanyarta take taimaka wa sel ɗaya amma tana iya cutar da na gaba.

Abin da masu binciken suka yi

Binciken ya haɗa nau’ikan shaida da dama, kuma kowannensu yana da iyakar abin da zai iya nuna.

• A cultured neurons. Sun kwatanta neurons na al’ada da neurons da ba su da Arc (Arc knockout), sannan suka auna yawan tau da ya fita a extracellular vesicles. Sun kuma gwada ko mayar da Arc—shi kaɗai ko tare da partner protein—yana sauya fitar tau.

• A mice. Sun yi amfani da sanannen model na tauopathy—rukunin cututtuka, ciki har da Alzheimer’s, inda tau yake canza tsari ya taru a kwakwalwa—wato rTg4510 mice. An ƙera waɗannan mice su samar da mutant form na human tau (P301L) da yawa. Masu binciken sun haɗa su da Arc-knockout mice, sannan suka ware vesicles daga brain tissue, suka auna tau da suke ɗauke da shi, kuma suka gwada ko tau ɗin har yanzu zai iya “seed” sabon aggregation.

• A seeding assay. An saka vesicles a kan reporter cells—engineered “biosensor” cells da ke bayar da fluorescence signal idan tau ya fara taruwa—domin a auna ƙarfin vesicle-borne tau wajen fara sabon aggregation.

• A human brain tissue. Sun binciki post-mortem prefrontal cortex daga mutane shida da ba su da Alzheimer’s da shida masu advanced disease (Braak stage six), suna duba ko Arc da phosphorylated tau suna tafiya tare a brain vesicles. Wannan kwatancin ya yiwu ne saboda donors da iyalansu sun bayar da brain tissue domin bincike, ciki har da mutanen da ba su da Alzheimer’s waɗanda suka samar da muhimmin comparison group.

• A matakin molecular. Ta amfani da purified proteins da all-atom simulations, sun gwada ko Arc yana ɗaure tau kai tsaye da kuma yadda wannan ɗaurin yake faruwa.

Abin da suka gano

• Arc yana da muhimmanci wajen saka tau cikin vesicles. Idan aka cire Arc daga neurons, tau da ke cikin vesicles ɗinsu yana raguwa sosai, ko da yake neurons ɗin suna ci gaba da samar da vesicles yadda ya kamata. A mice, brain vesicles daga dabbobin da ba su da Arc suna ɗauke da human tau kaɗan sosai. Rashin Arc bai rage overall vesicle production ba, don haka sakamakon ya shafi packing, ba samar da vesicles gaba ɗaya ba.

• Tau da Arc yake saka cikin vesicles yana iya seed sabon aggregation—kuma rashin Arc yana rage wannan sosai. Vesicles daga tau mice sun sa tau ya fara taruwa a reporter cells; vesicles daga Arc-knockout tau mice sun yi haka kaɗan ƙwarai. A kalmar marubutan, intercellular tau transmission ya zama “almost absent” idan babu Arc.

• Arc yana ɗaure tau kai tsaye, kuma ya fi son phosphorylated tau. Purified Arc ya ɗaure tau a direct, specific interaction, musamman idan tau ya kasance phosphorylated, wato yana ɗauke da ƙarin phosphate chemical tags da suke taruwa ba yadda ya kamata ba a cuta. Simulations sun nuna loose, shifting (“fuzzy”) complex, ba rigid lock ba.

• A vesicles daga kwakwalwar mutanen da ke da Alzheimer’s, Arc yana tafiya tare da tau mai alaƙa da cuta. Arc levels da phosphorylated-tau levels sun tashi da sauka tare a samples na Alzheimer’s (correlation coefficient 0.89, p-ƙima 0.01). A immunogold electron-microscopy imaging na vesicles daga brain guda ɗaya mai advanced Alzheimer’s (Braak stage six), 'yan kashi kaɗan ne suka ɗauki Arc da tau duka. Wannan na iya zama underestimate, domin manyan labels na tau ba sa shiga vesicles da kyau.

• Abin mamaki: rashin Arc ya sa neurons suka fi lalacewa, ba su fi kyau ba. Domin Arc yana fitar da tau daga sel, cire Arc ya sa ƙarin tau ya makale a cikin neurons. Arc-knockout tau mice sun tara ƙarin tau a cikin neurons kuma sun nuna ƙaramin ƙaruwa na cell death da wuri. Cire Arc shi kaɗai daga mice da ba su da tau transgene bai haifar da irin wannan asara ba. Saboda haka illar ta dogara da kasancewar tau da zai taru.

Abin da wannan bai tabbatar ba

kanun labarai game da Alzheimer’s suna yawan wuce ƙarfin shaidar, saboda haka iyakokin nan suna da muhimmanci.

• Wannan ba dalilin Alzheimer’s ba ne. Mechanism ne na mataki guda—yadda tau yake fita daga neurons cikin vesicles—a cikin labarin cutar da ya fi wannan girma kuma har yanzu ba a warware shi ba. Tau spread wani fasali ne na Alzheimer’s, ba asalinsa ba. Tau kuma yana aiki a cikin tsarin da ya haɗa amyloid, inflammation da sauran abubuwa.

• Ba magani ba ne, kuma ba ya nuna target guda mai sauƙi na magani. Ra’ayin da zai zo da sauri—“a toshe Arc”—shi ne daidai abin da double-edged sakamakon ke gargadi a kai: a waɗannan mice, hakan ya bar neurons suna riƙe ƙarin tau mai guba. Duk wani therapeutic idea daga nan ya fi “kashe Arc” rikitarwa sosai, kuma takardar ba ta gwada magani ba.

• Sakamakon mice ya fito daga tau-overexpression model, ba natural disease ba. rTg4510 mice an ƙera su su samar da mutant human tau da yawa a neurons. Model ne mai ƙarfi kuma standard domin nazarin tau spread, amma yana wakiltar tauopathy da engineered gene ya jawo, ba sporadic Alzheimer’s da yawancin marasa lafiya suke da shi ba.

• Shaidar mutane correlation ce, a ƙaramin sample. Ganin Arc da diseased tau suna tafiya tare a brain vesicles daga donors 12 ya dace da mechanism na mice, amma ba ya nuna kai tsaye cewa Arc ne ke tuƙa tau spread a mutane. Similar correlation a samples na mutanen da ba su da Alzheimer’s bai kai statistical significance ba. Correlation daga kwakwalwa 12 farawa ne, ba hukunci na ƙarshe ba.

• Vesicles ba su ne dukan hanyoyin fitar tau ba. Tau yana kuma barin neurons a matsayin free protein da wasu hanyoyi. takardar tana ba da strong case cewa Arc-vesicle pathway na da muhimmanci, ba cewa ita kaɗai ce hanya ba.

Yaya ƙarfin shaidar yake?

Ga babban ikirarin takardar—cewa Arc yana saka tau cikin vesicles kuma wannan yana da muhimmanci ga cell-to-cell tau transmission—shaidar tana da matakai da dama da ke goyon bayan juna: direct physical interaction, loss-of-function effect a cultured neurons, makamancin asara a mouse brain vesicles, functional seeding readout, da supporting human correlation. Mechanism ɗin bai dogara ga gwaji guda ɗaya ba, kuma control da ya nuna “packing, ba vesicle production ba” yana sa fassarar ta fi tsabta.

Babban rauni shi ne yadda za a faɗaɗa sakamakon. Strongest links suna cikin engineered mice da cultures; human bayanai correlation ce kuma ƙarama; therapeutic implication kuma ba ta da sauƙi domin mechanism ɗin yana da gefuna biyu. Abin da ya dace shi ne babban amincewa cewa Arc yana da muhimmanci ga vesicle-borne tau release a waɗannan systems, amma ƙaramin amincewa ga duk wani tsalle zuwa “dalilin Alzheimer’s” ko “hanyar magance shi.”

Akwai disclosure guda da ya kamata a ambata: corresponding marubuci na takardar ta bayyana commercial interests da suka shafi wannan mechanism—co-founder ne na company guda, kuma stockholder da consultant ne ga wata company da ke licensing intellectual property da patents da suka shafi Arc capsids.

Me ya sa wannan yake da muhimmanci

Idan tau spread yana da muhimmanci wajen yadda Alzheimer’s ke ci gaba, fahimtar kofofin da tau yake amfani da su wajen fita daga neurons muhimmin mataki ne kafin a iya tunanin rage yaduwar. Gano Arc a matsayin ɗaya daga cikin waɗannan kofofin—kuma, abin mamaki, kofar da ke taimaka wa neurons su zubar da tau mai guba—yana sake tsara wani ɓangare na matsalar. Yana nuna cewa anti-tau strategies da ke nufin vesicle release za su fuskanci trade-off, ba target mai sauƙi ba: idan ka dakatar da export, za ka iya kare maƙwabta amma ka bar source neuron da ƙarin guba.

Haka kuma binciken yana ƙara wani abin ban mamaki da ke tasowa a neuroscience: gene da kwakwalwarmu ta gaji daga wani tsohon virus-like element yana tsakiyar memory da neurodegeneration, yana jigilar kaya tsakanin neurons da sakamako mai kyau da mara kyau. Wannan ci gaba ne na gaske a fahimta—amma saboda yana matakin farko kuma yana da gefuna biyu, ba kyakkyawan tushe ba ne na yi wa kowa alkawarin cure.

Taƙaitaccen bayani

Masu binciken sun gano cewa Arc, neuronal gene da ya fito daga virus-like genetic element, yana ɗaure tau kai tsaye kuma yana saka shi cikin extracellular vesicles da neurons ke fitarwa. A cultured cells da tau-model mice, cire Arc ya rage seed-competent tau a brain vesicles sosai kuma ya kusan dakatar da transmission na tau daga sel zuwa sel; a post-mortem Alzheimer’s brains, Arc levels sun yi correlation da phosphorylated tau a vesicles. Abin mamaki shi ne cewa packing ɗin yana da gefuna biyu: yana fitar da tau mai guba daga neuron yayin da yake yaɗa seeds zuwa wasu, saboda haka mice da ba su da Arc sun tara ƙarin tau a cikin neurons kuma sun nuna ƙaramin ƙaruwa na early cell death. Binciken ya gano mechanism na yadda tau yake barin neurons, an nuna shi musamman a engineered mice da cells tare da supporting human correlation. Ba dalilin Alzheimer’s ba ne, ba therapy ba ne, kuma—saboda blocking Arc ya sa mouse neurons suka fi muni—ba mai sauƙi drug target ba ne.

Binciken ba tare da ƙarin gishiri ba

Abin da takardar ta nuna: A cultured neurons da tau-model mice, Arc yana da muhimmanci ga packing seed-competent tau cikin extracellular vesicles da transmission na tau tsakanin sel; Arc yana ɗaure tau kai tsaye; kuma a human Alzheimer’s brain vesicles, Arc levels suna correlation da phosphorylated tau.

Abin da yake da ma’ana amma ba a tabbatar ba: Arc-vesicle pathway na iya zama wata babbar hanyar tau spread a ainihin human Alzheimer’s disease. Human bayanai suna dacewa da wannan amma correlation ce kuma iyakantacciya.

Abin da bai nuna ba: Arc ne ke jawo Alzheimer’s; blocking Arc zai magance shi—idan wani abu, a waɗannan mice sakamakon ya nuna akasin haka; vesicles su ne hanya guda tilo da tau yake yaduwa; ko sakamakon tau-overexpressing mice zai koma kai tsaye ga sporadic human disease.

Manyan iyakoki: Mouse models suna over-produce mutant human tau; human sample kwakwalwa 12 ne bayan mutuwa tare da correlational readout, kuma correlation a controls bai kai statistical significance ba; ba a gwada therapy ba; sannan double-edged nature na mechanism yana rikitar da duk intervention.

Yaya yawan amincewa ya kamata mai karatu gaba ɗaya ya yi? Babban amincewa cewa Arc yana packing tau cikin vesicles kuma yana da muhimmanci ga tau release a waɗannan systems. Ƙaramin amincewa ga duk wani ikirarin cure ko cewa wannan ya bayyana dalilin Alzheimer’s disease.