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有毒蛋白Tau暴露-与阿尔茨海默病和神经退行性疾病相关

有毒蛋白Tau暴露-与阿尔茨海默病和神经退行性疾病相关

哥伦比亚大学领导的研究小组利用两项强大的技术来确定诊断和治疗神经退行性疾病的有希望的目标。

The+protein+tau+has+long+been+implicated+in+Alzheimer%26rsquo%3bs+and+a+host+of+other+debilitating+brain+diseases.+But+scientists+have+struggled+to+understand+exactly+how+tau+converts+from+its+normal%2c+functional+form+into+a+misfolded%2c+harmful+one.+Now%2c+researchers+at+Columbia+University%26rsquo%3bs+Zuckerman+Institute+and+Mayo+Clinic+in+Florida+have+used+cutting-edge+technologies+to+see+tau+in+unprecedented+detail.+By+analyzing+brain+tissue+from+patients%2c+this+research+team+has+revealed+that+modifications+to+the+tau+protein+may+influence+the+different+ways+it+can+misfold+in+a+person%26rsquo%3bs+brain+cells.+These+differences+are+closely+linked+to+the+type+of+neurodegenerative+disease+that+will+develop+%26mdash%3b+and+how+quickly+that+disease+will+spread+throughout+the+brain.%0aThe+study%2c+published+today+(February+6%2c+2020)+in+Cell%2c+employed+two+complementary+techniques+to+map+the+structure+of+tau+and+decipher+the+effects+of+additional+molecules%2c+called+post-translational+modifications+(PTMs)%2c+on+its+surface.+These+new+structural+insights+could+accelerate+the+fight+against+neurodegenerative+diseases%2c+by+helping+researchers+identify+new+biomarkers+that+detect+these+disorders+before+symptoms+arise+and+design+new+drugs+that+target+specific+PTMs%2c+preventing+the+onset+of+disease+before+it+wreaks+havoc+on+the+brain.%0a%26ldquo%3bTau+has+long+been+a+protein+of+significant+interest+due+to+its+prevalence+in+disease%2c%26rdquo%3b+said+Anthony+Fitzpatrick%2c+Ph.D.%2c+a+Principal+Investigator+at+Columbia%26rsquo%3bs+Mortimer+B.+Zuckerman+Mind+Brain+Behavior+Institute+who+led+the+study.+%26ldquo%3bIn+today%26rsquo%3bs+publication%2c+we+lay+out+compelling+evidence+that+PTMs+play+an+important+structural+role+in+tauopathies%2c+the+collection+of+neurodegenerative+diseases+characterized+by+toxic+buildup+of+misfolded+tau.%26rdquo%3b%0aNo+two+tauopathies+are+exactly+alike.+Each+affects+different+parts+of+the+brain+%26mdash%3b+even+different+cell+types+%26mdash%3b+which+can+lead+to+different+symptoms.+Alzheimer%26rsquo%3bs%2c+for+example%2c+arises+in+the+hippocampus%2c+and+so+affects+memory.+Chronic+traumatic+encephalopathy%2c+a+disorder+most+often+seen+in+survivors+of+traumatic+brain+injury%2c+can+lead+to+problems+with+movement%2c+memory+or+emotion%2c+depending+on+which+areas+of+the+brain+are+affected.%0aScientists+have+used+traditional+imaging+techniques+to+find+clues+to+how+tangles+of+tau%2c+comprised+of+inpidual+fibers%2c+or+filaments%2c+are+implicated+in+these+diseases.+But+painting+a+complete+picture+has+proven+difficult.%0a%26ldquo%3bThe+brains+of+patients+with+neurodegenerative+diseases+are+easy+to+identify%3a+entire+sections+have+been+eaten+away%2c+replaced+by+large+clumps+and+tangles+of+misfolded+proteins+like+tau%2c%26rdquo%3b+said+Tamta+Arakhamia%2c+an+undergraduate+at+Columbia%26rsquo%3bs+School+of+General+Studies%2c+a+research+assistant+in+the+Fitzpatrick+lab+and+the+paper%26rsquo%3bs+co-first+author.+%26ldquo%3bHowever%2c+tau+filaments+are+10%2c000+times+thinner+than+the+width+of+a+human+hair%2c+making+them+extraordinarily+difficult+to+study+in+detail.%26rdquo%3b%0aTo+address+this+challenge%2c+Dr.+Fitzpatrick+recently+pioneered+the+use+of+cryo-electron+microscopy%2c+or+cryo-EM%2c+to+visualize+inpidual+tau+filaments+from+diseased+human+brain+tissue.+Cryo-EM+is+a+Nobel+Prize-winning+technology+developed%2c+in+part%2c+by+researchers+at+Columbia+University.+Cryo-EM+images+samples+using+a+beam+of+electrons+and+has+proven+indispensable+for+investigations+into+extremely+small+biological+structures.+Using+cryo-EM%2c+Dr.+Fitzpatrick%26rsquo%3bs+team+has+reconstructed+the+structures+of+tau+filaments%2c+providing+new+insights+into+how+they+form%2c+grow%2c+and+spread+throughout+the+brain.%0aFor+all+its+ability+to+provide+highly+detailed+snapshots+of+proteins%2c+cryo-EM+has+limits.+To+overcome+these+limits%2c+Dr.+Fitzpatrick+and+his+team+to+paired+it+with+a+second+technology%3a+mass+spectrometry.%0a%26ldquo%3bCryo-EM+does+not+provide+a+complete+picture+because+it+cannot+fully+recognize+the+microscopic+PTMs+on+tau%26rsquo%3bs+surface%2c%26rdquo%3b+said+Christina+Lee%2c+an+undergraduate+student+at+Columbia+College%2c+a+research+assistant+in+the+Fitzpatrick+lab+and+the+paper%26rsquo%3bs+co-first+author.+%26ldquo%3bBut+mass+spectrometry+can+pinpoint+the+chemical+composition+of+PTMs+on+the+surface+of+tau.%26rdquo%3b%0aWorking+with+co-corresponding+author+Leonard+Petrucelli%2c+Ph.D.%2c+Ralph+B.+and+Ruth+K.+Abrams+Professor+of+Neuroscience+at+Mayo+Clinic+in+Florida%2c+and+Nicholas+Seyfried%2c+Ph.D.%2c+professor+of+biochemistry+at+Emory+University+School+of+Medicine%2c+the+researchers+used+cryo-EM+and+mass+spectrometry+to+analyze+the+brain+tissue+from+patients+diagnosed+with+two+tauopathies%3a+Alzheimer%26rsquo%3bs+disease+and+corticobasal+degeneration%2c+or+CBD.+CBD+is+a+rare+but+extremely+aggressive+tauopathy%2c+affecting+only+one+in+every+10%2c000+people.+Unlike+Alzheimer%26rsquo%3bs%2c+which+is+thought+to+arise+due+to+a+number+of+factors+including+tau%2c+CBD+is+primarily+associated+with+misbehaving+tau+proteins.%0a%26ldquo%3bStudying+a+primary+tauopathy+like+CBD+helps+us+to+figure+out+how+tau+becomes+toxic+to+brain+cells%2c%26rdquo%3b+said+Dr.+Petrucelli.+%26ldquo%3bWe+hope+to+extrapolate+that+knowledge+to+secondary+tauopathies%2c+such+as+Alzheimer%26rsquo%3bs+disease.%26rdquo%3b%0aThe+scientists%26rsquo%3b+analysis+of+brain+tissue+samples+revealed+several+key+insights.+Most+notably%2c+the+researchers+found+that+cross-talk+between+PTMs+on+the+surface+of+tau+influences+the+structure+of+the+tau+filaments%2c+contributing+to+differences+in+tau+filaments+observed+across+the+various+tauopathies+%26mdash%3b+and+even+variations+from+patient+to+patient.%0a%26ldquo%3bCollectively%2c+these+results+suggest+that+PTMs+may+not+only+be+serving+as+markers+on+the+proteins%26rsquo%3b+surface%2c+but+are+actually+influencing+the+behavior+of+tau%2c%26rdquo%3b+said+Dr.+Fitzpatrick%2c+who+is+also+an+assistant+professor+of+biochemistry+and+molecular+biophysics+at+Columbia%26rsquo%3bs+Vagelos+College+of+Physicians+and+Surgeons.%0aMoving+forward%2c+Dr.+Fitzpatrick+and+his+team+plan+to+expand+this+work+to+other+tauopathies.+Today%26rsquo%3bs+findings+on+Alzheimer%26rsquo%3bs+and+CBD+hold+immense+promise+for+the+field%2c+particularly+in+the+development+of+new+disease+models+%26mdash%3b+such+as+lab-grown+organoids%2c+or+mini-brains+%26mdash%3b+that+may+serve+to+accurately+recapitulate+what+is+actually+happening+in+the+brains+of+patients.%0a%26ldquo%3bOur+findings+will+inspire+new+approaches+for+developing+diagnostic+tools+and+designing+drugs%2c+such+as+targeting+PTM+vulnerabilities+to+slow+disease+progression%2c%26rdquo%3b+said+Dr.+Fitzpatrick%2c+who+is+also+a+member+of+Columbia%26rsquo%3bs+Taub+Institute+for+Research+on+Alzheimer%26rsquo%3bs+Disease+and+the+Aging+Brain.+%26ldquo%3bNeurodegenerative+diseases+are+among+the+most+complex+and+distressing+class+of+illnesses%2c+but+through+our+work+and+that+of+our+colleagues+and+collaborators%2c+we+are+building+a+roadmap+toward+successful+diagnostics+and+therapeutics.%26rdquo%3b%0aReference%3a+%26ldquo%3bPosttranslational+modifications+mediate+the+structural+persity+of+tauopathy+strains%26rdquo%3b+by+Tamta+Arakhamia%2c+Christina+E.+Lee%2c+Yari+Carlomagno%2c+Duc+M.+Duong%2c+Sean+R.+Kundinger%2c+Kevin+Wang%2c+Dewight+Williams%2c+Michael+DeTure%2c+Dennis+W.+Dickson%2c+Casey+N.+Cook%2c+Nicholas+T.+Seyfried%2c+Leonard+Petrucelli+and+Anthony+W.P.+Fitzpatrick%2c+6+February+2020%2c+Cell.%0aDOI%3a+10.1016%2fj.cell.2020.01.027%0aAdditional+contributors+include+Yari+Carlomagno%2c+Ph.D.%2c+Duc+Duong%2c+Sean+Kundinger%2c+Kevin+Wang%2c+Dewight+Williams%2c+Ph.D.%2c+Michael+DeTure%2c+Ph.D.%2c+Dennis+Dickson%2c+MD%2c+and+Casey+Cook%2c+Ph.D.%0aThis+research+was+supported+by+the+National+Institutes+of+Health%2fNational+Institute+of+Neurological+Disorders+and+Stroke+and+National+Institute+on+Aging+(U01NS110438%2c+RF1AG056151%2c+R35NS097273%2c+U01NS110438-02%2c+P01NS084974%2c+P01NS099114%2c+R01NS088689%2c+RF1AG062077-01%2c+RF1+AG062171-01%2c+U54NS100693%2c+R01AG053960%2c+R01AG061800%2c+U01AG046161%2c+U01AG061357%2c+S10RR23057%2c+S10OD018111%2c+U24GM116792)%2c+NYSTAR+and+the+NIH+(GM103310)%2c+the+National+Science+Foundation+(MRI+Grant+1531991%2c+DBI-1338135%2c+DMR-1548924)%2c+the+Simons+Foundation+(349247)%2c+the+Mayo+Clinic+Foundation%2c+the+Association+for+Frontotemporal+Degeneration%2c+the+Dana+Foundation%2c+and+the+Cure+Alzheimer%26rsquo%3bs+Fund.%0aThe+authors+report+no+financial+or+other+conflicts+of+interest.%0aColumbia+University%26rsquo%3bs+Mortimer+B.+Zuckerman+Mind+Brain+Behavior+Institute+brings+together+a+group+of+world-class+scientists+and+scholars+to+pursue+the+most+urgent+and+exciting+challenge+of+our+time%3a+understanding+the+brain+and+mind.+A+deeper+understanding+of+the+brain+promises+to+transform+human+health+and+society.+From+effective+treatments+for+disorders+like+Alzheimer%26rsquo%3bs%2c+Parkinson%26rsquo%3bs%2c+depression+and+autism+to+advances+in+fields+as+fundamental+as+computer+science%2c+economics%2c+law%2c+the+arts+and+social+policy%2c+the+potential+for+humanity+is+staggering.

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