线粒体在神经元程序性死亡中的作用新进展

神经元的死亡是许多神经系统疾病如阿尔茨海默病、帕金森病、急性青光眼等发生发展过程中的重要事件,传统认为,细胞死亡有凋亡、自噬、坏死三种方式,凋亡和自噬为程序性的细胞死亡,坏死为非程序性的死亡途径。而近年来的研究发现了一种名为程序性坏死(necroptosis)的可调控的坏死,因此,对这些可调控的细胞死亡的研究对治疗这类神经系统疾病有重要的意义。大量研究发现,在能量代谢和自由基代谢中占据着重要地位的线粒体在细胞死亡过程中也发挥重要作用。本文对线粒体在神经元凋亡、自噬和程序性坏死中的生物学作用的最新进展做一综述。     

Staurosporine Induces Programmed Cell Death in Embryonic Neurons and Activation of the Ceramide Pathway

Abstract: We activated the death pathway in embryonic chick cerebral hemisphere neuron (E7CH) cultures with staurosporine (0.1–1.0 µ M ) and observed the morphological changes, DNA laddering patterns, and DNA fragmentation (determined by Hoechst 33258 dye) associated with apoptosis. N -Acylsphingosine (C2-ceramide), a soluble ceramide analogue, was also able to induce apoptosis in these cells with the same characteristics and in the same time frame. We then observed that staurosporine was effective in inducing hydrolysis of sphingomyelin to ceramide as measured by a threefold increase in ceramide mass and increased incorporation of [³H]-palmitate into ceramide, concurrent with activating the cell death program. Furthermore, the coaddition of a specific ceramidase inhibitor, oleoylethanolamine (15 µ M ), enhanced the formation of ceramide as well as the degree of DNA fragmentation and cell death. Exogenous addition of sphingomyelinase activated the death pathway whereas ceramide glycanase did not, and inhibitors of sphingomyelin or protein synthesis failed to block this type of killing. Our data suggest that the formation of ceramide from sphingomyelin is a key event in staurosporine-induced and potentially all programmed cell death.     

Activation of Caspase-3 in Developmental Models of Programmed Cell Death in Neurons of the Substantia Nigra

Programmed cell death has been proposed to play a role in the death of neurons in acute and chronic degenerative neurologic disease. There is now evidence that the caspases, a family of cysteine proteases, mediate programmed cell death in various cells. In neurons, caspase-3 (CPP32/Yama/apopain), in particular, has been proposed to play a role. We examined the expression of caspase-3 in three models of programmed cell death affecting neurons of the substantia nigra in the rat: natural developmental neuron death and induced developmental death following either striatal target injury with quinolinic acid or dopamine terminal lesion with intrastriatal injection of 6-hydroxydopamine. Using an antibody to the large (p17) subunit of activated caspase-3, we have found that activated enzyme is expressed in apoptotic profiles in all models. Increased p17 immunostaining correlated with increased enzyme activity. The subcellular distribution of activated caspase-3 differed among the models: In natural cell death and the target injury model, it was strictly nuclear, whereas in the toxin model, it was also cytoplasmic. We conclude that p17 immunostaining is a useful marker for programmed cell death in neurons of the substantia nigra.     

Comparative Genomics Reveals Insights into the Divergent Evolution of Astigmatic Mites and Household Pest Adaptations

Highly diversified astigmatic mites comprise many medically important human household pests such as house dust mites causing ∼1–2% of all allergic diseases globally; however, their evolutionary origin and diverse lifestyles including reversible parasitism have not been illustrated at the genomic level, which hampers allergy prevention and our exploration of these household pests. Using six high-quality assembled and annotated genomes, this study not only refuted the monophyly of mites and ticks, but also thoroughly explored the divergence of Acariformes and the diversification of astigmatic mites. In monophyletic Acariformes, Prostigmata known as notorious plant pests first evolved, and then rapidly evolving Astigmata diverged from soil oribatid mites. Within astigmatic mites, a wide range of gene families rapidly expanded via tandem gene duplications, including ionotropic glutamate receptors, triacylglycerol lipases, serine proteases and UDP glucuronosyltransferases. Gene diversification after tandem duplications provides many genetic resources for adaptation to sensing environmental signals, digestion, and detoxification in rapidly changing household environments. Many gene decay events only occurred in the skin-burrowing parasitic mite Sarcoptes scabiei. Throughout the evolution of Acariformes, massive horizontal gene transfer events occurred in gene families such as UDP glucuronosyltransferases and several important fungal cell wall lytic enzymes, which enable detoxification and digestive functions and provide perfect drug targets for pest control. This comparative study sheds light on the divergent evolution and quick adaptation to human household environments of astigmatic mites and provides insights into the genetic adaptations and even control of human household pests.     

New Insights into the Molecular Mechanisms of Evolution: Stress Increases Genetic Diversity

The mechanisms of stress-induced mutagenesis in prokaryotes and realization of reserved (preaccumulated) genetic variation in eukaryotes are considered. In prokaryotes, replication becomes error-prone in stress because of the induction of the SOS response and the inactivation of the mismatch repair system; stress also increases the transposition rate and the efficiency of interspecific gene transfer. In eukaryotes, chaperone HSP90, which restores the native folding of mutant proteins (e.g., signal transduction and morphogenetic proteins) in normal conditions, fails to do so in stress, which leads to abrupt expression of multiple mutations earlier reserved in the corresponding genes. The role of these mechanisms in the evolution of prokaryotes and eukaryotes is discussed.