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帕金森病源于肠胃?科学家证实致病蛋白会从肠子爬进脑子

????本文来自微信公众号:学术经纬(ID:Global_Academia),作者:学术经纬,标题图来自视觉中国,
,越来越多的证据显示,帕金森病不仅是一种脑部病变,它与肠道存在联系。约翰·霍普金斯大学医学院的一支研究团队最近通过实验证明,帕金森病源于肠道,杀伤神经的蛋白会从肠道传到大脑。论文在线发表于权威学术期刊Neuron。这项工作也为治疗帕金森病提供了一个全新模型,可以用来检验预防疾病和阻止恶化的疗法。,
,,
,肠道问题早有端倪?,
,200年前,一位名叫詹姆斯·帕金森(James Parkinson)的外科医生报告了一种“令人烦躁和十分痛苦的疾病”,根据病人最突出的症状将其命名为“震颤性麻痹”。,
,与此同时,帕金森医生注意到,这些病人有便秘之苦。此外,在他描述的六个病例中,有一位服用治疗胃肠道的药物后似乎减轻了运动相关的问题。肠道在帕金森病中所起的作用或许在人们刚认识这种疾病时就埋下了伏笔。,
,今天的医生们也都注意到便秘是帕金森病最常见的症状之一,并且往往比运动障碍的发作更早出现。,
,,帕金森病是老年人中最常见的运动障碍疾病(图片来源:pixabay),
,然而,过去对帕金森病的研究和治疗一直集中于大脑。,
,科学家们发现,帕金森病患者的大脑有一个特征:一种被称为“α-突触核蛋白”(α-synuclein,α-syn)的蛋白质出现异常,错误折叠的蛋白质过量堆积在脑中,导致相关部位的神经细胞死亡。比如,在大脑的黑质,产生多巴胺的神经元死亡,使得调控运动、情绪等功能的关键神经递质——多巴胺减少。,
,2003年,德国神经解剖学家Heiko Braak教授在检查帕金森病患者的尸检结果时,意外地发现,除了大脑,在控制胃肠道的神经系统也有α-syn蛋白的堆积,并且出现时间对应于疾病发展的早期。因此,Braak教授曾大胆猜测,或许帕金森病起源于肠道?,
,不过,患者肠神经系统中的蛋白沉积和大脑中杀死神经元的蛋白沉积是相同的东西吗?如果是一回事儿,那么它们是怎么从肠子到脑子里的?帕金森病会像爬梯一样沿着连接肠道和大脑的神经,侵入大脑吗?当时并没有证据。,
,从肠子到大脑的“电缆”,
,在此次的新研究中,神经科学家Ted Dawson教授带领研究团队建立了一个新颖的动物模型回答了上述问题,终于在Braak教授提出假说十几年后,为“帕金森病源于肠胃”的设想提供了实验证据。,
,,本研究共同通讯作者Ted Dawson教授是神经退行性疾病领域的知名专家(图片来源:约翰·霍普金斯大学医学院),
,研究团队将合成的病理性α-syn蛋白注射到了几十只健康小鼠的胃肠道肌肉中。在注射后的1个月、3个月、7个月和10个月,他们取样分析了小鼠的脑组织。,
,结果显示,在注射1个月后,病理性α-syn蛋白已经扩散到大脑底部的脑干;3个月时,向上扩散到蓝斑和黑质,甚至还到达了杏仁核、下丘脑和前额叶;到7个月时,蔓延到更多的脑区,包括海马、纹状体和嗅球。蔓延的进程,正与Braak教授在人类帕金森病患者脑中观察到的病理发展相吻合!,
,,注射后不同时期,错误折叠的α-syn蛋白在中枢神经系统内扩散(图片来源:参考资料[1]),
,此外,在注射7个月后,伴随着病理性蛋白扩散到纹状体,脑成像技术显示,小鼠脑中生产多巴胺的神经元有了明显减少,这也正符合帕金森病患者的一个重要病理特点。,
,,脑成像显示,胃肠道注射病理蛋白后,小鼠大脑内多巴胺系统受损(图片来源:参考资料[1]),
,按Braak教授的观察和假设,帕金森病从胃肠道扩散到大脑,迷走神经可能是重要的途径。迷走神经从大脑底部的脑干发出,支配体内主要器官,包括胃肠道。,
,错误折叠的α-syn蛋白从肠道到大脑,走的是不是这条电缆通道呢?为了检验这一点,研究人员又做了一组实验。,
,同样是注射病理性α-syn蛋白,但这一次他们通过手术切断了小鼠的迷走神经。7个月之后,这些小鼠的脑内没有出现神经细胞被杀死的迹象。换句话说,被切断的神经似乎阻止了致病蛋白的前进。,
,,注射蛋白和切断迷走神经的示意图,研究团队优化了蛋白的注射部位和注射量(图片来源:参考资料[1]),
,随后,研究人员进一步考察这些生理改变是不是会导致动物出现行为上的变化。为此,他们让小鼠完成两项任务:筑巢和探索新环境。,
,筑巢需要精细灵巧的动作,对于曾在7个月前注射过病理性蛋白的小鼠来说,这项任务变得困难,它们做的窝又小又乱。“就像人类的帕金森病症状那样,控制精细运动的能力随着疾病发展而恶化。”共同通讯作者Hanseok Ko教授解释说。,
,另一项任务中,认知能力正常的小鼠会在实验设置的大盒子里好奇地四处探索,但受到病理性蛋白影响的小鼠们表现得非常焦虑,大部分时间待在盒子边缘。这种情形同样与帕金森病患者的症状相符。,
,相反,切断迷走神经、阻断病理性蛋白传播的小鼠们,表现与正常的小鼠类似,没有出现认知障碍。,
,,本研究的示意图(图片来源:Neuron),
,正因为看到帕金森病相关的早期特征和晚期特征、运动障碍和非运动障碍都在小鼠中得到了体现,研究团队相信,他们的结果可以为帕金森病的研究提供新的模型,例如,在早期症状的前阶段到全面恶化的整个过程中检验特定疗法的效果。,
,这些结果有力地支持了帕金森病源于肠道、传到大脑的假设。不过Ted Dawson教授看得更远:“第一,这项研究将激发未来肠-脑联系的更多研究;第二,对引起α-syn蛋白错误折叠和扩散的因素、分子或感染原因需要探索;第三,或许阻止α-syn蛋白从肠到脑的传播可以作为治疗时的一个目标。”他说。,
,我们期待科学家们的不断探索早日带来预防和治疗帕金森病的有效疗法!,
,参考资料:,[1] Sangjune Kim et al., (2019) Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson’s Disease. Neuron. DOI: 10.1016/j.neuron.2019.05.035,[2] New mouse model of Parkinson's disease shows how it spreads from the gut. Retrieved Jun 27, 2019, from https://www.eurekalert.org/pub_releases/2019-06/cp-nmm061919.php,[3] New research shows Parkinson's disease origins in the gut. Retrieved Jun 27, 2019, from https://www.eurekalert.org/pub_releases/2019-06/jhm-nrs061819.php,[4] Does Parkinson’s Begin in the Gut? Retrieved Jun 27, 2019, from https://www.scientificamerican.com/article/does-parkinsons-begin-in-the-gut/,[5] James Parkinson An Essay on the Shaking Palsy. Retrieved Jun 28, 2019 from https://neuro.psychiatryonline.org/doi/full/10.1176/jnp.14.2.223,
,本文来自微信公众号:学术经纬(ID:Global_Academia),作者:学术经纬,标题图来自视觉中国

ben wen lai zi wei xin gong zhong hao: xue shu jing wei ID: Global_Academia, zuo zhe: xue shu jing wei, biao ti tu lai zi shi jue zhong guo,, yue lai yue duo di zheng ju xian shi, pa jin sen bing bu jin shi yi zhong nao bu bing bian, ta yu chang dao cun zai lian xi. yue han huo pu jin si da xue yi xue yuan de yi zhi yan jiu tuan dui zui jin tong guo shi yan zheng ming, pa jin sen bing yuan yu chang dao, sha shang shen jing de dan bai hui cong chang dao chuan dao da nao. lun wen zai xian fa biao yu quan wei xue shu qi kan Neuron. zhe xiang gong zuo ye wei zhi liao pa jin sen bing ti gong le yi ge quan xin mo xing, ke yi yong lai jian yan yu fang ji bing he zu zhi e hua de liao fa.,,,, chang dao wen ti zao you duan ni?,, 200 nian qian, yi wei ming jiao zhan mu si pa jin sen James Parkinson de wai ke yi sheng bao gao le yi zhong" ling ren fan zao he shi fen tong ku de ji bing", gen ju bing ren zui tu chu de zheng zhuang jiang qi ming ming wei" zhen chan xing ma bi".,, yu ci tong shi, pa jin sen yi sheng zhu yi dao, zhei xie bing ren you bian mi zhi ku. ci wai, zai ta miao shu de liu ge bing li zhong, you yi wei fu yong zhi liao wei chang dao de yao wu hou si hu jian qing le yun dong xiang guan de wen ti. chang dao zai pa jin sen bing zhong suo qi de zuo yong huo xu zai ren men gang ren shi zhe zhong ji bing shi jiu mai xia le fu bi.,, jin tian de yi sheng men ye dou zhu yi dao bian mi shi pa jin sen bing zui chang jian de zheng zhuang zhi yi, bing qie wang wang bi yun dong zhang ai de fa zuo geng zao chu xian.,,, pa jin sen bing shi lao nian ren zhong zui chang jian de yun dong zhang ai ji bing tu pian lai yuan: pixabay,, ran er, guo qu dui pa jin sen bing de yan jiu he zhi liao yi zhi ji zhong yu da nao.,, ke xue jia men fa xian, pa jin sen bing huan zhe de da nao you yi ge te zheng: yi zhong bei cheng wei" tu chu he dan bai" synuclein, syn de dan bai zhi chu xian yi chang, cuo wu zhe die de dan bai zhi guo liang dui ji zai nao zhong, dao zhi xiang guan bu wei de shen jing xi bao si wang. bi ru, zai da nao de hei zhi, chan sheng duo ba an de shen jing yuan si wang, shi de tiao kong yun dong qing xu deng gong neng de guan jian shen jing di zhi duo ba an jian shao.,, 2003 nian, de guo shen jing jie pou xue jia Heiko Braak jiao shou zai jian cha pa jin sen bing huan zhe de shi jian jie guo shi, yi wai di fa xian, chu le da nao, zai kong zhi wei chang dao de shen jing xi tong ye you syn dan bai de dui ji, bing qie chu xian shi jian dui ying yu ji bing fa zhan de zao qi. yin ci, Braak jiao shou ceng da dan cai ce, huo xu pa jin sen bing qi yuan yu chang dao?,, bu guo, huan zhe chang shen jing xi tong zhong de dan bai chen ji he da nao zhong sha si shen jing yuan de dan bai chen ji shi xiang tong de dong xi ma? ru guo shi yi hui shi er, na me ta men shi zen me cong chang zi dao nao zi li de? pa jin sen bing hui xiang pa ti yi yang yan zhe lian jie chang dao he da nao de shen jing, qin ru da nao ma? dang shi bing mei you zheng ju.,, cong chang zi dao da nao de" dian lan",, zai ci ci de xin yan jiu zhong, shen jing ke xue jia Ted Dawson jiao shou dai ling yan jiu tuan dui jian li le yi ge xin ying de dong wu mo xing hui da le shang shu wen ti, zhong yu zai Braak jiao shou ti chu jia shuo shi ji nian hou, wei" pa jin sen bing yuan yu chang wei" de she xiang ti gong le shi yan zheng ju.,,, ben yan jiu gong tong tong xun zuo zhe Ted Dawson jiao shou shi shen jing tui xing xing ji bing ling yu de zhi ming zhuan jia tu pian lai yuan: yue han huo pu jin si da xue yi xue yuan,, yan jiu tuan dui jiang he cheng de bing li xing syn dan bai zhu she dao le ji shi zhi jian kang xiao shu de wei chang dao ji rou zhong. zai zhu she hou de 1 ge yue 3 ge yue 7 ge yue he 10 ge yue, ta men qu yang fen xi le xiao shu de nao zu zhi.,, jie guo xian shi, zai zhu she 1 ge yue hou, bing li xing syn dan bai yi jing kuo san dao da nao di bu de nao gan 3 ge yue shi, xiang shang kuo san dao lan ban he hei zhi, shen zhi hai dao da le xing ren he xia qiu nao he qian e ye dao 7 ge yue shi, man yan dao geng duo de nao qu, bao kuo hai ma wen zhuang ti he xiu qiu. man yan de jin cheng, zheng yu Braak jiao shou zai ren lei pa jin sen bing huan zhe nao zhong guan cha dao de bing li fa zhan xiang wen he!,,, zhu she hou bu tong shi qi, cuo wu zhe die de syn dan bai zai zhong shu shen jing xi tong nei kuo san tu pian lai yuan: can kao zi liao 1,, ci wai, zai zhu she 7 ge yue hou, ban sui zhe bing li xing dan bai kuo san dao wen zhuang ti, nao cheng xiang ji shu xian shi, xiao shu nao zhong sheng chan duo ba an de shen jing yuan you le ming xian jian shao, zhe ye zheng fu he pa jin sen bing huan zhe de yi ge zhong yao bing li te dian.,,, nao cheng xiang xian shi, wei chang dao zhu she bing li dan bai hou, xiao shu da nao nei duo ba an xi tong shou sun tu pian lai yuan: can kao zi liao 1,, an Braak jiao shou de guan cha he jia she, pa jin sen bing cong wei chang dao kuo san dao da nao, mi zou shen jing ke neng shi zhong yao de tu jing. mi zou shen jing cong da nao di bu de nao gan fa chu, zhi pei ti nei zhu yao qi guan, bao kuo wei chang dao.,, cuo wu zhe die de syn dan bai cong chang dao dao da nao, zou de shi bu shi zhe tiao dian lan tong dao ne? wei le jian yan zhe yi dian, yan jiu ren yuan you zuo le yi zu shi yan.,, tong yang shi zhu she bing li xing syn dan bai, dan zhe yi ci ta men tong guo shou shu qie duan le xiao shu de mi zou shen jing. 7 ge yue zhi hou, zhei xie xiao shu de nao nei mei you chu xian shen jing xi bao bei sha si de ji xiang. huan ju hua shuo, bei qie duan de shen jing si hu zu zhi le zhi bing dan bai de qian jin.,,, zhu she dan bai he qie duan mi zou shen jing de shi yi tu, yan jiu tuan dui you hua le dan bai de zhu she bu wei he zhu she liang tu pian lai yuan: can kao zi liao 1,, sui hou, yan jiu ren yuan jin yi bu kao cha zhei xie sheng li gai bian shi bu shi hui dao zhi dong wu chu xian xing wei shang de bian hua. wei ci, ta men rang xiao shu wan cheng liang xiang ren wu: zhu chao he tan suo xin huan jing.,, zhu chao xu yao jing xi ling qiao de dong zuo, dui yu ceng zai 7 ge yue qian zhu she guo bing li xing dan bai de xiao shu lai shuo, zhe xiang ren wu bian de kun nan, ta men zuo de wo you xiao you luan." jiu xiang ren lei de pa jin sen bing zheng zhuang na yang, kong zhi jing xi yun dong de neng li sui zhe ji bing fa zhan er e hua." gong tong tong xun zuo zhe Hanseok Ko jiao shou jie shi shuo.,, ling yi xiang ren wu zhong, ren zhi neng li zheng chang de xiao shu hui zai shi yan she zhi de da he zi li hao qi di si chu tan suo, dan shou dao bing li xing dan bai ying xiang de xiao shu men biao xian de fei chang jiao lv, da bu fen shi jian dai zai he zi bian yuan. zhe zhong qing xing tong yang yu pa jin sen bing huan zhe de zheng zhuang xiang fu.,, xiang fan, qie duan mi zou shen jing zu duan bing li xing dan bai chuan bo de xiao shu men, biao xian yu zheng chang de xiao shu lei si, mei you chu xian ren zhi zhang ai.,,, ben yan jiu de shi yi tu tu pian lai yuan: Neuron,, zheng yin wei kan dao pa jin sen bing xiang guan de zao qi te zheng he wan qi te zheng yun dong zhang ai he fei yun dong zhang ai dou zai xiao shu zhong de dao le ti xian, yan jiu tuan dui xiang xin, ta men de jie guo ke yi wei pa jin sen bing de yan jiu ti gong xin de mo xing, li ru, zai zao qi zheng zhuang de qian jie duan dao quan mian e hua de zheng ge guo cheng zhong jian yan te ding liao fa de xiao guo.,, zhei xie jie guo you li di zhi chi le pa jin sen bing yuan yu chang dao chuan dao da nao de jia she. bu guo Ted Dawson jiao shou kan de geng yuan:" di yi, zhe xiang yan jiu jiang ji fa wei lai chang nao lian xi de geng duo yan jiu di er, dui yin qi syn dan bai cuo wu zhe die he kuo san de yin su fen zi huo gan ran yuan yin xu yao tan suo di san, huo xu zu zhi syn dan bai cong chang dao nao de chuan bo ke yi zuo wei zhi liao shi de yi ge mu biao." ta shuo.,, wo men qi dai ke xue jia men de bu duan tan suo zao ri dai lai yu fang he zhi liao pa jin sen bing de you xiao liao fa!,, can kao zi liao:, 1 Sangjune Kim et al., 2019 Transneuronal Propagation of Pathologic Synuclein from the Gut to the Brain Models Parkinson' s Disease. Neuron. DOI: 10. 1016 j. neuron. 2019. 05. 035, 2 New mouse model of Parkinson 39 s disease shows how it spreads from the gut. Retrieved Jun 27, 2019, from https: www. eurekalert. org pub_releases 201906 cpnmm061919. php, 3 New research shows Parkinson 39 s disease origins in the gut. Retrieved Jun 27, 2019, from https: www. eurekalert. org pub_releases 201906 jhmnrs061819. php, 4 Does Parkinson' s Begin in the Gut? Retrieved Jun 27, 2019, from https: www. scientificamerican. com article doesparkinsonsbegininthegut, 5 James Parkinson An Essay on the Shaking Palsy. Retrieved Jun 28, 2019 from https: neuro. psychiatryonline. org doi full 10. 1176 jnp. 14. 2. 223,, ben wen lai zi wei xin gong zhong hao: xue shu jing wei ID: Global_Academia, zuo zhe: xue shu jing wei, biao ti tu lai zi shi jue zhong guo

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