抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

In both metazoan development and metastatic cancer, migrating cells must carry out a detailed, complex program of sensing cues, binding substrates, and moving their cytoskeletons. The linker cell in Caenorhabditis elegans males undergoes a stereotyped migration that guides gonad organogenesis, occurs with precise timing, and requires the nuclear hormone receptor NHR-67. To better understand how this occurs, we performed RNA-seq of individually staged and dissected linker cells, comparing transcriptomes from linker cells of third-stage (L3) larvae, fourth-stage (L4) larvae, and nhr-67-RNAi–treated L4 larvae. We observed expression of 8,000–10,000 genes in the linker cell, 22–25% of which were up- or down-regulated 20-fold during development by NHR-67. Of genes that we tested by RNAi, 22% (45 of 204) were required for normal shape and migration, suggesting that many NHR-67–dependent, linker cell-enriched genes play roles in this migration. One unexpected class of genes up-regulated by NHR-67 was tandem pore potassium channels, which are required for normal linker-cell migration. We also found phenotypes for genes with human orthologs but no previously described migratory function. Our results provide an extensive catalog of genes that act in a migrating cell, identify unique molecular functions involved in nematode cell migration, and suggest similar functions in humans.

https://science.sciencemag.org/content/sci/256/5054/184.full.pdf

Alzheimer's disease: the amyloid cascade hypothesis

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

Parkinson's disease is a common neurodegenerative disease with complex clinical features1. Autosomal recessive juvenile parkinsonism (AR-JP)2,3 maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253 (ref. 4); the former is deleted in one Japanese AR-JP patient5. By positional cloning within this microdeletion, we have now isolated a complementary DNA clone of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3–7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product ‘Parkin’.

Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism

Parkinson's disease: Mechanisms and models

Neurotensin is a basic tridecapeptide that was originally isolated from bovine hypothalamus by Leeman and her colleagues.' Subsequently this group has also isolated and sequenced neurotensin from both human and bovine small intestine.2, s Radioimmunological and immunocytochemical studies have demonstrated that neurotensin-like immunoreactivity (NTLI) is localized to specific cells in anterior pi t~i tary,~. and In the mammalian brain, neurotensin is concentrated in vesicles within synaptic terminalsg. 7 * I * and it can be released from regions rich in NTLI by depolarizing l4 Furthermore, neurotensin binding sites have been demonstrated by autoradiographicis and biochemical techniques1\"IH and shown to be localized in regions where NTLI is concentrated. Together with the observations that neurotensin has direct effects when applied to single neurons in regions where binding sites are these data are consistent with the view that neurotensin may be a neurotransmitter in the central nervous system.*l In the gastrointestinal tract, neurotensin is localized in endocrine-like cells of the gut mucosa with highest concentrations in the ileum. It is one candidate for the so far elusive hormone enterogasterone.\"-\" In order to investigate possible functions of neurotensin and to characterize the NTLI in the brain, pituitary gland, and peripheral tissues of the rat, we have developed antisera specific for the carboxy-terminal and amino-terminal sequences of NTl-,,.6. 24 These antisera have also been used to follow the degradation of neurotensin by rat brain synaptic membranes. It would be an additional support for a neurotransmitter role of neurotensin in the central nervous system if neurotensin could be shown to be rapidly degraded by synaptic membranes as this would provide a means for rapid inactivation.\

Neurotensin: regional distribution, characterization, and inactivation.

Effects of antibodies against nerve growth factor on the postnatal development of substance P-containing sensory neurons.

Tau and Parkinson disease.

Mutations in the coding and intronic regions of the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Some of these mutations lead to an overproduction of tau isoforms with four microtubule-binding repeats, followed by the development of fibrillary lesions and selective cell death. In order to analyze the development of these neurofibrillary lesions in transgenic mice, the longest four-repeat human brain tau isoform was expressed under control of two different neuron-specific promoters. In a first model, utilizing the human Thyl promoter, transgenic tau was hyperphosphorylated and abnormally localized to cell bodies and dendrites. In a second model, which made use of a human Thy1.2 expression vector, transgenic expression levels were much higher, and an additional phenotype was observed: Large numbers of pathologically enlarged axons containing neurofilament- and tau-immunoreactive spheroids were present, especially in spinal cord. Signs of Wallerian degeneration and neurogenic muscle atrophy were observed. Behaviorally, transgenic mice showed signs of muscle weakness. Our data show that overexpression of human four-repeat tau in itself is sufficient to lead to nerve cell dysfunction and amyotrophy. We have now extended our initial studies by introducing exonic mutations including G2t 2V and PS01L into the tau gene in order to achieve a more advanced FTDP-17 associated phenotype.

Michel Goedert

Papers

Neurotensin: regional distribution, characterization, and inactivation.

Effects of antibodies against nerve growth factor on the postnatal development of substance P-containing sensory neurons.

Tau and Parkinson disease.

In vivo analysis of wild-type and FTDP-17 tau transgenic mice.

Human tau isoforms confer distinct morphological and functional properties to stably transfected fibroblasts