生物谷報道：細胞死亡至少可以分為細胞凋亡和細胞壞死這兩種主要形式。壞死,，作為細胞死亡的一種新途徑,，在7月份的《自然—化學生物學》上有相關的研究進展介紹。壞死是人體病變中的一種普遍特征,，不像細胞凋亡現(xiàn)象被認為是細胞對外來傷害的一種被動反應,。Junying Yuan及其同事發(fā)現(xiàn)了一種導致細胞壞死的細胞代謝新途徑，他們稱之為necroptosis,。該研究小組發(fā)現(xiàn),，當沒有足夠的血液達到大腦時，也就是發(fā)生缺血性腦傷害時，細胞壞死將會發(fā)生,。
雖然過去數十年,，研究工作者發(fā)現(xiàn)了細胞凋亡的重要機制，但是在實驗中,，人們也能發(fā)現(xiàn)一些奇怪的現(xiàn)象,，如非凋亡的程序性死亡。經典的理論認為,，細胞凋亡是程序化的,，而細胞壞死則是突發(fā)性的，被動的,。本周Nature Chemical Biology, 上刊登了華人袁鈞英教授及其同事的新的發(fā)現(xiàn),，通過體外以及小鼠的腦缺血的體內模型均觀察到一種非凋亡的程序性死亡的新現(xiàn)象。
近來,，有關帶有壞死特征的非凋亡性細胞死亡的研究報道變得越來越多,。但是，研究者們并沒有合適的工具來進行有關這些現(xiàn)象的潛在機制研究,。要解決這些問題,，Yuan及其同事找到了一種化學因子Nec-1，它具有抑制這種非凋亡性程序性細胞死亡的專一性,。他們發(fā)現(xiàn),，Nec-1阻止了所有的這類細胞死亡，表明了導致細胞壞死的necroptosis的這一細胞代謝途徑確實是存在的,。他們進一步發(fā)現(xiàn),，在小鼠模型中Nec-1減少了缺血性腦傷害的程度。對于遭受擊打后的腦傷害病人,，Nec-1應該是一種很有前景的治療方向,。此外，Nec-1還為以后的研究者提供了一種非常重要的化學研究工具來進行相關研究,。
對于此項研究,，各界細胞生物學家給予了極高的評價。Rockefeller University教授Shai Shaham,告訴記者：“以往已發(fā)現(xiàn)很多類似的現(xiàn)象,，但是一直沒有合適的工具來研究這種機制,，也不知道哪些蛋白質參與這一過程”。以前發(fā)現(xiàn)經典的Fas/TNFR的細胞凋亡信號通路能激活caspases家族很多蛋白質,，從而誘導細胞凋亡的發(fā)生,，但是，如果阻止了caspase活性,，但是細胞出現(xiàn)了壞死,，而不是凋亡,。Georgetown University醫(yī)學中心Alan Faden說，“這些現(xiàn)象說明了細胞凋亡中確實存在壞死樣的類型”,。但是人們卻不知道是什么物質在其中起作用,，袁鈞英對記者說，我們回答了這樣一個問題：我們發(fā)現(xiàn)了什么物質抑制了這些細胞的死亡,。
袁鈞英及其同事篩選了大約15000種化合物,，發(fā)現(xiàn)了這種小分子能抑制這種特殊形式的細胞死亡。命名為necrostatin-1或Nec-1,，能抑制TNF誘導的細胞壞死,。這也是第一次提供另一種細胞程序性死亡的有力證據。Faden告訴記者,，“看樣子這是一條新的途徑,，這是極其優(yōu)秀的發(fā)現(xiàn)”,。
袁鈞英認為,，這種非凋亡性程序性死亡在中風病人身上會有發(fā)生，新的Nec-1有望抑制這種現(xiàn)象的發(fā)生,，從而為將來研究相關的藥物,，甚至臨床應用提供有力的證據。不過Shaham認為這條新的途徑并非與經典的途徑毫無關系,，而認為它們可能同相互作用,，共同導致細胞損傷。他認為袁鈞英教授這篇文章提供了一條重要的線索是促進人們尋找如何阻止這種程序性死亡的發(fā)生的方法,。生物谷專家認為,，袁鈞英教授這項發(fā)現(xiàn)不僅使人們重新認識了細胞凋亡的過程，也使人們意識到細胞的死亡過程可能是非常復雜的行為,。即獨立于細胞凋亡和壞死之外還會存在第三種類型,。這也為預防和治療損傷類疾病提供新的治療依據。
Reference:
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology. 29 May 2005. http://www.nature.com/nchembio/
A.G. Yakolev, A.I. Faden, "Mechanisms of neural cell death: Implications for development of neuroprotective treatment strategies," Neurorx, 1:5-16, January 2004. [PubMed Abstract]
Junying Yuan http://cellbio.med.harvard.edu/faculty/yuan/
Shai Shaham http://www.rockefeller.edu/labheads/shaham/shaham-lab.php
H. Matsumura et al., "Necrotic death pathway in Fas receptor signaling," J Chem Biol, 151:1247-56, December 11, 2000. [PubMed Abstract]
Alan I. Faden http://www.neuro.georgetown.edu/faden.htm
E.H. Lo et al., "Mechanisms, challenges and opportunities in stroke," Nat Rev Neurosci. 4:399-415, May 2003. [PubMed Abstract]
附：
袁鈞英教授簡介
Department of Cell Biology
Harvard Medical School
240 Longwood Avenue
Boston, MA 02115
Junying Yuan received her Ph.D. in Neuroscience from Harvard University in 1989 and her undergraduate degree from Fudan University, Shanghai, China, in 1982. Dr. Yuan carried out her postdoctoral research at the Massachusetts Institute of Technology. She was first appointed as Assistant Professor at Harvard Medical School in 1992, when she became a Principal Investigator of the Cardiovascular Research Center at Massachusetts General Hospital. She joined the Department of Cell Biology in 1996 and was appointed a Professor of Cell Biology at Harvard Medical School in 2000.
袁鈞英教授在線蟲發(fā)育,，細胞凋亡研究中均有一系列重大發(fā)現(xiàn),。尤其是發(fā)現(xiàn)了caspase家族的眾多成員，是國際公認的細胞凋亡領域研究權威,，近年來在鋅指蛋白,，細胞凋亡新蛋白研究中屢有突破性進展。文章雖不多,，但多以Cell, Nature上居多,，質量十分高。
生物谷內以往對袁鈞英教授的相關介紹及報道：
袁鈞英博士簡介
袁鈞英的文章欣賞
有關人員對袁鈞英教授此文的評論：
評論1
The paper by Degterev et al. is a tour de force characterization of necroptosis, a non-apoptotic form of programmed cell death that involves necrosis and autophagy. Existence of this caspase-independent pathway was hypothesized from observations that several different cultured cell types undergo a common necrotic death upon stimulation of death domain receptor proteins in the presence of caspase inhibitors. To investigate a necroptosis pathway, the authors performed a chemical screen of 15,000 small molecules for necroptosis inhibition. Of these, a heterocyclic compound, Necrostatin-1 (Nec-1), was shown to be a very potent and specific inhibitor of necroptosis.
Application of Nec-1 did not block apoptosis, autophagy, or oxidative stress-induced necrosis, and also did not disrupt normal cellular physiology. Significantly, necroptosis was shown to be a delayed component of ischemia-associated neuronal cell death induced by cerebral artery occlusion in mice. Administration of Nec-1 attenuated the extent of ischemia-induced neuronal death and did not disrupt general brain physiology. Furthermore, Nec-1 exhibited an extended time window of protection and was able to exert its effects 6 hours after the onset of injury. The simultaneous addition of Nec-1 and the zVAD.fmk caspase inhibitor yielded an additive protective effect, suggesting a potentially effective therapeutic combination.
Overall, necroptosis has a delayed latency compared to apoptosis, and the authors hypothesize that it may act as a redundant mechanism to provide cells with an ability to die when they find themselves in an environment non-permissive to apoptosis. Future studies to determine the site of Nec-1 action and characterize the components of necroptosis pathway promise to provide important insight not only into a conserved and important mechanism for cell death, but also to develop effective treatments for a variety of human pathologies.
評論2
Two general mechanisms of cell death have been described: programmed cell death and necrosis. Programmed cell death, or apoptosis, is a directed program that proceeds through specific signal transduction pathways common to different cell types. In particular, apoptosis initiates a sequential activation of multiple caspases. In contrast, the alternative to programmed cell death, necrosis, is thought to be a nondirected cellular response to overwhelming stress. Therapeutic strategies to prevent cell death in pathological conditions have targeted apoptosis rather than necrosis, because of the perception that necrosis is unregulated and relatively nonspecific. However, recent reports have implicated specific signal transduction pathways, such as stimulation of death domain receptors (DRs) by their ligands, in necrotic cell death. In a paper that is stunning in its elegance and simplicity, Degterev et al. build on these observations by identifying a new type of programmed cell death that resembles necrosis but is distinct from both apoptosis and necrosis. They call it necroptosis.
The authors had followed the growing number of studies suggesting that under certain situations, DR-induced cell death, which normally proceeds via an apoptotic pathway, is not prevented by caspase inhibitors and resembles necrosis. Because this caspase-independent DR-induced cell death led to similar necrotic morphological features in a wide variety of cell types, Degterev and collaborators suspected the involvement of a non-apoptotic programmed signal transduction pathway shared by multiple cell types. They chose an ingenious way to find out whether such a pathway actually exists. Cells treated simultaneously with the DR agonist TNFα and a pan-caspase inhibitor, a combination the authors used to devise an operational definition of necroptosis, were used to screen a library of chemical compounds for inhibitors of the death of these cells. The screen resulted in the selection of a molecule dubbed necrostatin-1 (Nec-1).
The authors then used Nec-1 to answer a number of questions about this new pathway that they called necroptosis. First, they asked whether this pathway was indeed distinct from apoptosis. When cells are exposed to FasL (Fas ligand), they exhibit classic symptoms of apoptosis. Stimulation of cells with FasL in the presence of a pan-caspase inhibitor, in contrast, leads to morphological symptoms of necrosis. The authors showed that Nec-1 did not inhibit apoptotic morphology (cytoplasm condensation, chromatin marginalization, nuclear fragmentation, and plasma membrane blebbing) displayed by FasL-treated cells. However, Nec-1 did inhibit the appearance of necrotic morphology (nuclear condensation, organelle swelling, and early loss of plasma membrane integrity) displayed by cells exposed to FasL in the presence of the caspase inhibitor zVAD.fmk. Of special interest was the fact that the onset of apoptosis in response to FasL was faster than the onset of necroptosis in response to FasL in conjunction with zVAD.fmk. The authors suggest that apoptosis usually conceals or forestalls necroptosis because of its faster kinetics.
The authors then asked whether necroptotic cell death utilized factors involved in known cell death signaling pathways. They compared the activity of Nec-1 with that of small-molecule inhibitors of such factors as calpains, calcium homeostasis perturbation, PARP, and nitric oxide synthase. None of the tested compounds inhibited necroptosis in all cell types, as Nec-1 does, establishing the uniqueness of the necroptotic pathway. Furthermore, necroptosis was not inhibited by antioxidants, nor did Nec-1 block the classic necrosis caused by the cell stressor menadione, showing the independence of necroptosis from oxidative stress.
Neuronal cell death caused by ischemic brain injury is known to display some non-apoptotic features, and the participation of DRs in ischemic cell death has been postulated. The authors thought that perhaps ischemia produces conditions that are more conducive to necroptosis than to apoptosis. So they administered Nec-1 intracerebroventricularly to mice that had undergone middle cerebral artery occlusion (MCAO), a model for inducing ischemic damage in mice. Strikingly, Nec-1 reduced the infarct volume without blocking caspase 3 activation, showing that at least a portion of the cell death resulting from MCAO is necroptotic.
A growing body of evidence supports the idea that apoptosis is at least one means by which neurons die in Alzheimer disease (AD). However, a number of studies have described non-apoptotic features of AD neurodegeneration. Furthermore, DRs have been implicated both in neuritic degeneration in AD brain and in neuronal death induced by β-amyloid (e.g., Morishima et al., 2001). It is possible that necroptosis also plays a role in AD neurodegeneration. It will be interesting to assess the effect of Nec-1 on neuropathology in mouse transgenic models of AD, or on neurodegeneration in in vitro models of AD neurodegeneration. If necroptosis is shown to be a component of AD pathology, a new world of therapeutic strategies, aimed at necroptotic pathways, would be opened up for this devastating disease.
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