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In 2006, TAR-DNA binding protein 43 kDa (TDP-43) was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.

Mutations in the profilin 1 ( PFN1 ) gene, which is crucial for the conversion of monomeric to filamentous actin, can cause familial amyotrophic lateral sclerosis, suggesting that alterations in cytoskeletal pathways contribute to disease pathogenesis. Genetics of familial amyotrophic lateral sclerosis In nearly half of the familial cases of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), the genetic basis remains unknown. These authors show that mutations in the profilin 1 ( PFN1 ) gene, which is essential for the conversion of monomeric to filamentous actin, can cause familial ALS. The available data suggest that alterations in cytoskeletal pathways contribute to the pathogenesis of ALS. The observation of PFN1 mutations in ALS has immediate implications for diagnostic testing of familial ALS cases and provides a novel potential target for the treatment of ALS. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 ( PFN1 ) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.

Familial amyotrophic lateral sclerosis (FALS) has been linked to mutations in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1). Assay by transient expression in primate cells of six FALS mutant enzymes revealed a continuum of enzymatic activity bounded by the enzyme carrying the mutation Gly-85 → Arg, which was inactive, and mutant enzyme G37R carrying the Gly-37 → Arg change, which retained full specific activity but displayed a 2-fold reduction in polypeptide stability. The G37R mutant displayed similar properties in transformed lymphocytes from an individual heterozygous for the G37R and wild-type SOD1 genes; heterodimeric enzymes composed of mutant and wild-type subunits were detected, but there was no measurable diminution in the stability and activity of the wild-type subunits. Thus, for mutants such as G37R, either surprisingly modest losses in activity (involving only the mutant subunit) can yield motor neuron death, or alternatively, mutant SOD1 may acquire properties that injure motor neurons by one or more mechanisms unrelated to the metabolism of oxygen radicals.

Mammalian neurofilaments comprise three polypeptide subunits, NF-L (61 kd), NF-M (100 kd) and NF-H (110 kd), which share a structure typical of intermediate filament polypeptides: a short N-terminal domain, a central$\\alpha$ -helical domain, and a C-terminal domain of variable length. Each subunit incorporates multiple phosphates: estimates range from 1-3 for NF-L, 6-18 for NF-M and 12-60 for NF-H. As a step toward understanding the mechanism and function of neurofilament phosphorylation, I have identified certain phosphorylation sites in these polypeptides. By purifying and sequencing phosphopeptides that were generated by proteolytic digestion of neurofilament proteins and identified by phosphatase treatment and specific chemical modification, I have identified one site in NF-L and six sites in NF-M that are phosphorylated extensively in vivo. All of these sites are located in the C-terminal domain, suggesting a function that is specific to this region. The sites in NF-L and NF-M that are phosphorylated in vivo were also phosphorylated in vitro by the kinase activity associated with a Triton-X-100 insoluble neurofilament preparation. Preliminary investigations of this kinase activity showed that it is stimulated by magnesium, but is not affected by cAMP, cGMP, Ca $\\sp{++}$ -calmodulin Ca $\\sp{++}$ -diacylglycerol-phosphatidylserine, and heparin, suggesting that the major activity in this preparation is not from those kinases that are affected by these factors. When kinase activity was extracted from this cytoskeleton preparation by a solution of KBr, it preferred native NF-H compared to dephosphorylated NF-H as its substrate. To investigate the function of the C-terminal region of NF-H, we purified this domain and examined its structure by electronmicroscopy after rotary shadowing. We observed that the C-terminal domain is a linear and extended structure, consistent with the idea that this region extends from the filament core and forms cross bridges. These results provide criteria for the future identification of the neurofilament kinases and are relevant to considerations regarding the function of neurofilament phosphorylation.

Cyclocarya paliurus as a multiple function plant can accumulate biologically important microelement elements.To reveal the variation of selected microelement concentrations in leaves of C.paliurus provenances during the growing season,12 C.paliurus provenances in the field trial were sampled five times at approximately 1-month intervals.The method of inductively coupled plasma optical emission spectrometer（ICP-OES） was employed to determinate average concentrations of Fe,Mn,Zn,Cu and Se in leaves of 12 C.paliurus provenances.The results show that on average,the concentrations of five microelement in the leaves follows an order of Fe Mn Zn Cu Se.Variance analysis shows that there are significant differences in Fe,Mn and Zn concentrations among the twelve provenances（p0.05）,while there is no significant difference between Cu and Se concentrations.A significant difference was also observed in the concentrations of five microelements at the different sampling times（p0.001）,but the mean concentrations for each microelement showed different temporal dynamic patterns.Meanwhile,a significant correlation between concentrations of Se and other measured microelements was detected in the leaves of C.paliurus,except for Mn.Obtained results not only demonstrated that leaves of C.paliurus exhibited higher levels of microelements（Fe,Mn,Cu,Zn and Se）,but also provided a basis for breeding strategies of superior provenances with rich content of microelements,and choosing optimum harvesting time for food industry in future.

研究了等渗的盐和水分胁迫及其钙调节下,青钱柳幼苗叶肉细胞中ATP酶活性在亚细胞中的分布及其超微结构变化。在人工气候室中采用水培法,将青钱柳幼苗进行5个不同浓度处理：对照,85mMNaCl,85mMNaCl＋12mMCa（NO3）2,PEG（渗透势等于85mMNaCl）及PEG（渗透势等于85mMNaCI）＋12mMCa（NO3）2。结果表明：正常生长条件下,ATP酶活性较低并主要定位在细胞核中 等渗胁迫12d以后,ATP酶活性增大并以液泡中居多。等渗水分胁迫下出现的嗜锇颗粒较等渗盐胁迫下的多。由于外源钙的调节作用,等渗胁迫下ATP酶活性增加并主要转移至细胞核上,且在等渗水分胁迫下的嗜锇颗粒明显减少。ATP酶定位在细胞核中表明幼苗遭受胁迫伤害程度较轻,而定位在液泡中则表明受伤害程度较重。等渗处理4和20d后,等渗胁迫及其钙调节下青钱柳幼苗叶片超微结构被破坏程度较无钙调节处理,尤其是较等渗水分胁迫下的轻。初步认为,等渗盐胁迫下青钱柳幼苗遭受的胁迫伤害程度较等渗水分胁迫下的轻,而钙调节作用则以等渗水分胁迫下的效果较佳。