這是摘自最新一期Neuron文章,，同期共發(fā)表相似的內(nèi)容文章3篇，可見這一領(lǐng)域的熱度,。局部蛋白質(zhì)合成,，或局部第二信使的變化,，介導(dǎo)局部的信號(hào)轉(zhuǎn)導(dǎo)，從而產(chǎn)生特定的功能,，這解釋了為什么同一物質(zhì)能分別介導(dǎo)多種不同信號(hào),，仍能保證每種信號(hào)的特異性，而不會(huì)相互confusion,。當(dāng)然,，我個(gè)人認(rèn)為信號(hào)應(yīng)該是三維特征的，即具有時(shí)間性,，空間性和量的變化,，同一種信號(hào)分子，如MAPK,，在不同時(shí)間,，細(xì)胞內(nèi)不同的位置，以及它表達(dá)時(shí)不同的量都可能介導(dǎo)不同的信號(hào)傳遞,，也正因?yàn)樾盘?hào)分子三維特征,，保證了信號(hào)傳遞的精確性和特異性，也保證了細(xì)胞內(nèi)只需要幾十條信號(hào)途徑便能介導(dǎo)成千上萬種stress的信號(hào)傳遞,。

Neuron, Vol 40, 347-359, 9 October 2003

Compartmentalized Synthesis and Degradation of Proteins in Neurons
Oswald Steward *1 and Erin M. Schuman *2

A cornerstone of our understanding of the neuron as a cell came from findings in the late 19th century that axons and dendrites grew out from the cell body, and depended on the cell body for their survival. These findings led Ramon y Cajal to conclude that the cell body was the “trophic center of the neuron.” Later cell biological studies revealed that the machinery for macromolecular synthesis and posttranslational processing was present in neuronal cell bodies, and that there were selective axonal and dendritic transport mechanisms capable of delivering proteins anywhere within neurons. Together, these discoveries led to a central tenet of neuronal cell biology—that the protein building blocks of axons and dendrites were synthesized exclusively in the soma, and transported to their final destinations.

In the early 1980s, however, there was increasing evidence for an alternative view that certain proteins could be synthesized outside the neuronal cell body using mRNAs that were selectively positioned in particular cytoplasmic microdomains. A story line on dendritic protein synthesis was launched by the discovery that polyribosomes and associated membranous cisterns were selectively localized beneath postsynaptic sites on dendrites (Steward, 1983; Steward and Fass, 1983; Steward and Levy, 1982). The selectivity of the localization suggested that (1) synapse-associated polyribosomes synthesized key molecular constituents of the synapse, (2) local translation was regulated by signaling events at the synapse, and (3) local translation played a key role in synapse plasticity. Studies over the last 21 years have confirmed and extended these hypotheses (Steward and Schuman, 2001).

Running in parallel with the story of local protein synthesis in dendrites was a story line that developed in fits and starts regarding local protein synthesis in axons. There was consistent evidence for axonal protein synthesis in invertebrate systems (reviewed in Alvarez et al., 2000), but whether similar mechanisms existed in vertebrate axons remained controversial. Recent studies, however, have established the existence of protein synthetic machinery and mRNAs in growing vertebrate axons, especially growth cones, and demonstrated that this machinery and the local protein synthesis it allows plays a key role in growth cone function (for a review, see Steward, 2002).

A key advantage conferred by mechanisms that allow local protein synthesis is the ability to regulate protein composition in local domains on a moment-by-moment basis. If this is advantageous, it is obvious to ask whether there are also mechanisms that could mediate local protein degradation. The story here is less developed, but recent evidence indicates that such mechanisms do exist, and are important for neuronal function.

Here, we summarize what is known about the mechanisms for local protein synthesis and degradation, highlighting some of the key unresolved questions. We focus here on cell biological issues, and mention only briefly the role of local synthesis in synaptic plasticity, which has been considered in other recent reviews (Steward and Schuman, 2001).

Machinery for Local Translation in Dendrites
Structural features of organelles provide important clues about their function, and so we begin with a consideration of the features of synapse-associated polyribosome complexes (SPRCs). Electron microscopic analyses revealed that the majority of the polyribosomes in dendrites are selectively positioned beneath postsynaptic sites (Steward and Levy, 1982). At spine synapses, SPRCs are most often localized at the base of the spine in the small mound-like structures from which the neck of the spine emerges. At nonspine synapses (both excitatory and inhibitory), SPRCs are localized beneath the postsynaptic membrane specialization (Steward et al., 1996). In their location beneath the synapse, SPRCs are ideally situated to be influenced by ionic and/or chemical signals from the synapse as well as by events within the dendrite proper. An important implication of this selective localization is that there must be some mechanism that causes ribosomes, mRNA, and other components of the translational machinery to dock selectively in the postsynaptic cytoplasm. The details of the mechanisms underlying this selective localization remain to be established.

Local Translation: Ubiquitous or Synapse Specific?
What proportion of synapses has underlying SPRCs? Estimates vary depending on the quantitative methods used and the cell type being evaluated. Reconstructions of dendrites in the dentate gyrus of adult rats reveal that about 25% of the spine synapses on mid-proximo-distal dendrites have underlying polyribosomes (Steward and Levy, 1982). The incidence was higher at synapses on proximal dendrites. Studies of ribosomes (not polyribosomes) in serially reconstructed spines revealed that most spines on pyramidal neurons in the cerebral cortex contained ribosomes, whereas the incidence of ribosomes was lower in spines on cerebellar Purkinje cells (Spacek and Hartmann, 1983). Thus, the prevalence of subsynaptic ribosomes varies by neuron type.

The incidence of polyribosomes also varies across development. During periods of maximal synaptogenesis, most synapses have underlying polyribosomes, and many synapses have multiple clusters, implying that local synthesis is especially important during periods of synapse growth (Steward and Falk, 1986).

The fact that polyribosomes are present at some, but not all synapses in mature animals raises the question of whether SPRCs can shuttle from one synapse to another, or whether the presence of the machinery marks synapses that are capable of, and in the process of, local translation. It is of interest in this regard that following synaptic stimulation leading to LTP in the CA1 region of the hippocampus, polyribosomes appear to translocate from the base of the spine into the spine head (Ostroff et al., 2002). These results document that polyribosome localization can be modified by signals generated at the synapse, but leave open whether polyribosomes can move from one synapse to another. Also unknown is whether a given polyribosome moves as a unit, or whether the individual ribosomes dissociate from the polyribosome, move, and then reinitiate on some other mRNA.

Definitive Evidence for Local Synthesis
To definitively establish that protein synthesis is indeed occurring in local compartments, be it dendrites or axons, the cell body must be ruled out as a protein synthesis source. Studies using synaptodendrosomes or neurosomes are inadequate in this regard because these are usually contaminated by fragments of cell bodies and glia. A capacity for local incorporation of amino acid precursors has been documented in physically isolated dendrites (Torre and Steward, 1992), and recent studies have shown that physically and optically isolated dendrites are capable of synthesizing GFP-tagged proteins (Aakalu et al., 2001; Job and Eberwine, 2001) and that dendritic synthesis was stimulated by BDNF. Interestingly, there were persistent hotspots for protein synthesis along the length of the dendrite that were located near ribosomes and synapses, lending support to the idea that dendritic sources of protein synthesis may subserve a small synaptic domain.

Presence of Elements of the ER and Golgi in Dendrites
Integral membrane proteins (receptors, for example) and proteins for release are synthesized by rough endoplasmic reticulum (RER), and are usually glycosylated. Thus, an important issue has been whether ribosomes are present on membranes in an RER-like configuration, and whether ER and Golgi enzymes are present that could mediate posttranslational modifications. Reconstructions of dendrites of dentate granule cells and hippocampal pyramidal cells indicate that about 50% of the polyribosomes beneath synapses are associated with tubular cisterns, suggesting that the SPRC/cisternal complex may be a form of RER (Steward and Reeves, 1988). Immunocytochemical studies have revealed the presence of different markers of the RER in dendrites of neurons in culture, including ribophorin I (Torre and Steward, 1996), the signal sequence receptor TRAPP, and the signal recognition particle (SRP), which directs nascent polypeptide chains to the RER (Tiedge and Brosius, 1996). Electron microscopic immunocytochemical studies indicate that the membranous cisterns that are present near spine synapses stain for Sec6Iα protein complex, which is part of the machinery for translocation of proteins through the RER during their synthesis (Pierce et al., 2000). Moreover, dendrites that have been separated from their cell body incorporate sugar