研究：漸凍人病因 蛋白質輸送受阻【台灣醒報╱記者李昀澔╱台北報導】 2014.04.06 10:24 pm 美國團隊發現了「漸凍人」等神經退化性疾病的成因之一！威斯康辛大學團隊發表於《細胞：幹細胞》的研究指出，神經細胞內負責「運送」蛋白質的構造「神經絲」出現異常，很可能是造成蛋白質「糾結」在細胞內，導致神經萎縮、甚至死亡的原因。罕見疾病肌萎縮性脊髓側索硬化症（ALS），也就是俗稱漸凍人的發生率，約為10萬分之5，病因包括基因突變、部分胺基酸代謝異常引發毒性、細胞內「粒線體」結構異常、細胞表面鈉及鉀離子通道功能受損等，目前學界多認為漸凍人神經受損，係由多種原因共同導致。漸凍人最可怕的症狀，就是在患者神智完全清醒的狀態下日漸癱軟，包括行走、說話、吞嚥，甚至呼吸的「力氣」都逐漸失去；近代理論物理大師史蒂芬霍金，以及美國職棒大聯盟鐵人代表之一的魯蓋瑞，都是運動神經系統完全損壞的典型患者。威斯康辛大學團隊針對ALS的研究，係從神經細胞內部物質傳遞切入；若將神經細胞比喻為「章魚」，頭部代表細胞本體，也就是「細胞核」所在的部位，則由細胞體製造的蛋白質，會順著「四肢」，也就是「軸索」送往「肢端」並釋出，藉此控制整個生理運作。部分在「製程」中出錯，導致結構「畸形」的蛋白質，常會阻塞蛋白質沿著軸索輸送的途徑，軸索就會逐漸萎縮，嚴重者更可能造成細胞死亡。研究人員發現，另一個蛋白質無法在細胞內部順暢運送的原因，是細胞內的高速公路「神經絲」結構出現異常，研究團隊進一步在細胞實驗中發現，透過調控基因「導正」神經絲結構，可改善軸索萎縮的情形，可望作為未來治療研究的基礎。另一方面，蛋白質無法運輸而在細胞內部阻塞的情形，不只發生在漸凍人，包括阿茲海默症、帕金森氏症等神經退化性疾病，都有類似現象，研究人員據此推論，神經絲結構異常，很可能是多種神經退化性疾病的「第一步」。 【2014/04/06 台灣醒報】
Study helps unravel the tangled origin of ALS April 3, 2014 by David Tenenbaum In this microscope photo of motor neurons created in the laboratory of Su-Chun Zhang, green marks the nucleus and red marks the nerve fibers. Zhang and co-workers at the Waisman Center have identified a misregulation of protein in the nucleus as the likely first step in the pathology of ALS. By studying nerve cells that originated in patients with a severe neurological disease, a University of Wisconsin-Madison researcher has pinpointed an error in protein formation that could be the root of amyotrophic lateral sclerosis. Also called Lou Gehrig's disease, ALS causes paralysis and death. According to the ALS Association, as many as 30,000 Americans are living with ALS. After a genetic mutation was discovered in a small group of ALS patients, scientists transferred that gene to animals and began to search for drugs that might treat those animals. But that approach has yet to work, says Su-Chun Zhang, a neuroscientist at the Waisman Center at UW-Madison, who is senior author of the new report, published April 3 in the journal Cell Stem Cell. Zhang has been using a different approach — studying diseased human cells in lab dishes. Those cells, called motor neurons, direct muscles to contract and are the site of failure in ALS. About 10 years ago, Zhang was the first in the world to grow motor neurons from human embryonic stem cells. More recently, he updated that approach by transforming skin cells into iPS (induced pluripotent stem) cells that were transformed, in turn, into motor neurons. IPS cells can be used as "disease models," as they carry many of the same traits as their donor. Zhang says the iPS approach offers a key advantage over the genetic approach, which "can only study the results of a known disease-causing gene. With iPS, you can take a cell from any patient, and grow up motor neurons that have ALS. That offers a new way to look at the basic disease pathology." In the new report, Zhang, Waisman scientist Hong Chen, and colleagues have pointed a finger at proteins that build a transport structure inside the motor neurons. Called neurofilament, this structure moves chemicals and cellular subunits to the far reaches of the nerve cell. The cargo needing movement includes neurotransmitters, which signal the muscles, and mitochondria, which process energy. Motor neurons that control foot muscles are about three feet long, so neurotransmitters must be moved a yard from their origin in the cell body to the location where they can signal the muscles, Zhang says. A patient lacking this connection becomes paralyzed; tellingly, the first sign of ALS is often paralysis in the feet and legs. Scientists have known for some time that in ALS, "tangles" along the nerve's projections, formed of misshapen protein, block the passage along the nerve fibers, eventually causing the nerve fiber to malfunction and die. The core of the new discovery is the source of these tangles: a shortage of one of the three proteins in the neurofilament. The neurofilament combines structural and functional roles, Zhang says. "Like the studs, joists and rafters of a house, the neurofilament is the backbone of the cell, but it's constantly changing. These proteins need to be shipped from the cell body, where they are produced, to the most distant part, and then be shipped back for recycling. If the proteins cannot form correctly and be transported easily, they form tangles that cause a cascade of problems." Finding neurofilament tangles in an autopsy of an ALS patient "will not tell you how they happen, when or why they happen," Zhang says. But with millions of cells — all carrying the human disease — to work with, Zhang's research group discovered the source of the tangles in the protein subunits that compose the neurofilaments. "Our discovery here is that the disease ALS is caused by misregulation of one step in the production of the neurofilament," he says."We can put this into action right away. The basic research is now starting to pay off. With a disease like this, there is no time to waste."Beyond ALS, Zhang says "very similar tangles" appear in Alzheimer's and Parkinson's diseases. "We got really excited at the idea that when you study ALS, you may be looking at the root of many neurodegenerative disorders." While working with motor neurons sourced in stem cells from patients, Zhang says he and his colleagues saw "quite an amazing thing. The motor neurons we reprogrammed from patient skin cells were relatively young, and we found that the misregulation happens very early, which means it is the most likely cause of this disease. Nobody knew this before, but we think if you can target this early step in pathology, you can potentially rescue the nerve cell." In the experiment just reported, Zhang found a way to rescue the neural cells living in his lab dishes. When his group "edited" the gene that directs formation of the deficient protein, "suddenly the cells looked normal," Zhang says. Already, he reports, scientists at the Small Molecule Screening and Synthesis Facility at UW-Madison are looking for a way to rescue diseased motor neurons. These neurons are made by the millions from stem cells using techniques that Zhang has perfected over the years. Zhang says "libraries" of candidate drugs, each containing a thousand or more compounds, are being tested. "This is exciting. We can put this into action right away. The basic research is now starting to pay off. With a disease like this, there is no time to waste."
科學家培養出人腦中最普遍的星狀細胞 Scientists cultivate human brain's most ubiquitous cell in lab dish
http://www.physorg.com/news/2011-05-scientists-cultivate-human-brain-ubiquitous.html May 22, 2011 殘念啊，卑微的星狀細胞（astrocyte），人類神經系統中最常見的細胞。雖然長久以來被認為不過是腦與脊髓中的補土（putty，油灰），不過在神經科學家之中，這種星形的星狀細胞已被發現新的細節。他們確認它在腦中有許多功能，更別提它在一系列中樞神經系統失調中所扮演的角色了。現在，寫在當期（5/22）Nature Biotechnology 期刊中，一群由 Wisconsin-Madison 大學幹細胞研究者 Su-Chun Zhang（張素春）所領導的小組報告，他們能在實驗室培養皿中直接將胚胎以及被誘導的人類幹細胞變成星狀細胞。Zhang 解釋，這種能夠製造大型、一批均一的星狀細胞的能力，為完全理解這種腦中最平凡細胞的功能性角色，及其涉及到的一堆中樞神經系統失調（從頭痛到癡呆），開啟了一條新途徑。此外，能夠培養這些細胞，賦予研究者一種強大的工具，為神經性失調發明新療法與藥物。"這些細胞還沒有得到許多關注，因為人類星狀細胞很難獲得，" Zhang 表示，UW-Madison Waisman 中心研究者以及 UW-Madison 醫學與公衛系神經科學教授。"但我們能從單一個幹細胞製造出十億或上兆個它們。"與神經元（這種大型絲狀細胞，負責處理與傳遞資訊）相較，神經星狀細胞雖然受到冷落，不過當科學家更了解它們在腦中的角色後，他們已將注意力轉向這種更常見的細胞。這裡有各種類型的星狀細胞，而且它們肩負著非常基本的環境維持（housekeeping）任務，例如調控血流、吸收互動中的神經元所製造出來的過量化學物質以及控制著血腦屏障（blood-brain barrier），那是一種專門的過濾器，能將危險的分子阻絕在整個腦部之外。星狀細胞，某些研究指出，若考慮到它們在人腦中體積比其他動物物種要大上許多，它們甚至可能在人類智能中扮演某種角色。"若無星狀細胞，神經元將無法作用，" Zhang 提到。"星狀細胞將整個神經細胞包覆起來以保護它們並使之健康。它們幾乎參與了腦中的各種功能或失調。"根據 Zhang 表示，能在實驗室中打造星狀細胞，有數種有潛力的實用成果。它們能當成篩檢器，確認用以治療腦疾的新藥物，在培養皿中，它們能被用來塑模疾病，而且，在不久的將來，有可能移植這些細胞以治療各種神經性疾病，包括腦瘤、帕金森氏症、以及脊髓損傷。為了臨床使用而製備的星狀細胞很有可能是第一批被移植以介入神經性疾病的細胞。當運動神經元受到致命的肌萎縮性脊髓側索硬化症（ALS，漸凍人，又稱 Lou Gehrig's disease）影響時，會被裹在星狀細胞中。"當受傷或罹患神經性疾病時，腦中的神經元更辛苦地運作，而且這麼做會它們製造出更多神經傳導物質，" 那些化學物質如果過量對腦中其他細胞來說會是毒素，Zhang 說。"有個構想是，如果將正常、健康的星狀細胞置於腦中，有可能拯救運動神經元，" 根據 Zhang 表示。"這些細胞成為治療標的時真的很有用。"由 Wisconsin 小組所開發的技術立下製造各種不同種類之星狀細胞的基礎。此外，也有可能在遺傳上改造它們藉此模擬疾病，使得那些之前無法接觸的神經性疾病能在實驗室中被研究。
Source: http://only-perception.blogspot.tw/2011/05/blog-post_23.html
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