Feb 2017, Volume 12 Issue 1
    

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  • MINI-REVIEW
    Molecular and genetic insights into an infantile epileptic encephalopathy – CDKL5 disorder
    Ailing Zhou,Song Han,Zhaolan Joe Zhou
    2017, 12(1): 1-6. https://doi.org/10.1007/s11515-016-1438-7
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    BACKGROUND: The discovery that mutations in cyclin-dependent kinase-like 5 (CDKL5) gene are associated with infantile epileptic encephalopathy has stimulated world-wide research effort to understand the molecular and genetic basis of CDKL5 disorder. Given the large number of literature published thus far, this review aims to summarize current genetic studies, draw a consensus on proposed molecular functions, and point to gaps of knowledge in CDKL5 research.

    METHODS: A systematic review process was conducted using the PubMed search engine focusing on CDKL5 studies in the recent ten years. We analyzed these publications and summarized the findings into four sections: genetic studies, CDKL5 expression patterns, molecular functions, and animal models. We also discussed challenges and future directions in each section.

    RESULTS: On the clinical side, CDKL5 disorder is characterized by early onset epileptic seizures, intellectual disability, and stereotypical behaviors. On the research side, a series of molecular and genetic studies in human patients, cell cultures and animal models have established the causality of CDKL5 to the infantile epileptic encephalopathy, and pointed to a key role for CDKL5 in regulating neuronal function in the brain. Mouse models of CDKL5 disorder have also been developed, and notably, manifest behavioral phenotypes, mimicking numerous clinical symptoms of CDKL5 disorder and advancing CDKL5 research to the preclinical stage.

    CONCLUSIONS: Given what we have learned thus far, future identification of robust, quantitative, and sensitive outcome measures would be the key in animal model studies, particularly in heterozygous females. In the meantime, molecular and cellular studies of CDKL5 should focus on mechanism-based investigation and aim to uncover druggable targets that offer the potential to rescue or ameliorate CDKL5 disorder-related phenotypes.

  • REVIEW
    Intracellular organelle networks: Understanding their organization and communication through systems-level modeling and analysis
    Qinle Ba,Ge Yang
    2017, 12(1): 7-18. https://doi.org/10.1007/s11515-016-1436-9
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    BACKGROUND: Membrane-bound intracellular organelles are biochemically distinct compartments used by eukaryotic cells for serving specialized physiological functions and organizing their internal environment. Recent studies revealed surprisingly extensive communication between these organelles and highlighted the network nature of their organization and communication. Since organization and communication of the organelles are carried out at the systems level through their networks, systems-level studies are essential for understanding the underlying mechanisms.

    METHODS: We reviewed recent studies that used systems-level quantitative modeling and analysis to understand organization and communication of intracellular organelle networks.

    RESULTS: We first review modeling and analysis studies on how fusion/fission and degradation/biogenesis, two essential and closely related classes of activities of individual organelles, collectively mediate the dynamic organization of their networks. We then turn to another important aspect of the dynamic organization of the organelle networks, namely how organelles are physically connected within their networks, a property referred to as the topology of the networks in mathematics, and summarize some of their distinct properties. Lastly, we briefly review modeling and analysis studies that aim to understand communication between different organelle networks, focusing on cellular calcium homeostasis as an example. We conclude with a brief discussion of future directions for research in this area.

    CONCLUSIONS: Together, the reviewed studies provide critical insights into how diverse activities of individual organelles collectively mediate the organization and communication of their networks. They demonstrate the essential role of systems-level modeling and analysis in understanding complex behavior of such networks.

  • REVIEW
    Putting it all together: intrinsic and extrinsic mechanisms governing proteasome biogenesis
    Lauren A. Howell,Robert J. Tomko Jr.,Andrew R. Kusmierczyk
    2017, 12(1): 19-48. https://doi.org/10.1007/s11515-017-1439-1
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    BACKGROUND: The 26S proteasome is at the heart of the ubiquitin-proteasome system, which is the key cellular pathway for the regulated degradation of proteins and enforcement of protein quality control. The 26S proteasome is an unusually large and complicated protease comprising a 28-subunit core particle (CP) capped by one or two 19-subunit regulatory particles (RP). Multiple activities within the RP process incoming ubiquitinated substrates for eventual degradation by the barrel-shaped CP. The large size and elaborate architecture of the proteasome have made it an exceptional model for understanding mechanistic themes in macromolecular assembly.

    OBJECTIVE: In the present work, we highlight the most recent mechanistic insights into proteasome assembly, with particular emphasis on intrinsic and extrinsic factors regulating proteasome biogenesis. We also describe new and exciting questions arising about how proteasome assembly is regulated and deregulated in normal and diseased cells.

    METHODS: A comprehensive literature search using the PubMed search engine was performed, and key findings yielding mechanistic insight into proteasome assembly were included in this review.

    RESULTS: Key recent studies have revealed that proteasome biogenesis is dependent upon intrinsic features of the subunits themselves as well as extrinsic factors, many of which function as dedicated chaperones.

    CONCLUSION: Cells rely on a diverse set of mechanistic strategies to ensure the rapid, efficient, and faithful assembly of proteasomes from their cognate subunits. Importantly, physiological as well as pathological changes to proteasome assembly are emerging as exciting paradigms to alter protein degradation in vivo.

  • REVIEW
    Mechanisms of genome instability in Hutchinson-Gilford progeria
    Haoyue Zhang,Kan Cao
    2017, 12(1): 49-62. https://doi.org/10.1007/s11515-016-1435-x
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    BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disorder. It arises from a single point mutation in the LMNA gene. This mutation stimulates an aberrant splicing event and produces progerin, an isoform of the lamin A protein. Accumulation of progerin disrupts numerous physiological pathways and induces defects in nuclear architecture, gene expression, histone modification, cell cycle regulation, mitochondrial functionality, genome integrity and much more.

    OBJECTIVE: Among these phenotypes, genomic instability is tightly associated with physiological aging and considered a main contributor to the premature aging phenotypes. However, our understanding of the underlying molecular mechanisms of progerin-caused genome instability is far from clear.

    RESULTS AND CONCLUSION: In this review, we summarize some of the recent findings and discuss potential mechanisms through which, progerin affects DNA damage repair and leads to genome integrity.

  • RESEARCH ARTICLE
    Association between microRNA-21, microRNA-150, and microRNA-451 expression and clinical outcome of patients with acute lymphoblastic leukemia
    Ali Amin Asnafi,Elahe Khodadi,Neda Golchin,Arash Alghasi,Yousef Tavakolifar,Najmaldin Saki
    2017, 12(1): 63-70. https://doi.org/10.1007/s11515-016-1437-8
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    BACKGROUND: Acute lymphoblastic leukemia (ALL) occurs owing to the defective maturation, increased proliferation, and lack of differentiation of lymphoid cells. Evaluation of the expression levels of microRNAs (miRNAs) could help in the prognosis and improve the clinical outcome of ALL patients. Given the role of miR-21, miR-150, and miR-451 as oncogenes and tumor suppressors in lymphocytes, this study explored the relation between the expression levels of these miRNAs and the clinical outcomes of ALL patients.

    METHODS: cDNA synthesis and RT-PCR were performed for peripheral blood samples from 41 patients with ALL, as well as for U937 and Jurkat cell lines to examine the expression of miR-451, miR-150, and miR-21 after miRNA purification. We also performed an epidemiological analysis in which Mann–Whitney and Chi-square tests were used to investigate the relationship between the expression of miRNAs and other clinical and laboratory data. Binary logistic regression models were used to estimate the odds ratio in univariate and multivariate analyses for clinical outcomes.

    RESULTS: miR-21 and miR-150 expression was found to be decreased, while miR-451 expression showed no difference compared to the control group. There was a significant relationship between miR-451 expression and hemoglobin (Hb) levels, as well as between miR-150 expression and clinical outcomes of ALL patients.

    CONCLUSION: Increased expression of miR-451 decreased the Hb levels; reduced expression of miR-150 was associated with increased relapse rate in patients. Age, increased WBC, and decreased Hb levels were associated with increased relapse rates in ALL patients. Therefore, miR-150 could be used as a biomarker to determine the clinical outcome of ALL patients.

  • RESEARCH ARTICLE
    Complete mitochondrial genome of Ampittia dioscorides (Lepidoptera: Hesperiidae) and its phylogenetic analysis
    Xin-Min Qin,Xiao-Wen Yang,Li-Xia Hou,Hui-Min Li
    2017, 12(1): 71-81. https://doi.org/10.1007/s11515-016-1434-y
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    The complete mitochondrial genome of Ampittia dioscorides (Lepidoptera: Hesperiidae) was determined. The sequenced genome is a circular molecule of 15313 bp, containing 13 protein-coding genes (PCGs), 22 tRNA genes, two rRNA genes, and an A+ T-rich region. The gene arrangements and transcribing directions are identical to those in most of the reported lepidopteran mitogenomes. The base composition of the whole genome and genes or regions are also similar to those in other lepidopteran species. All the PCGs are initiated by typical ATN codons; the exception being COI, which begins with a CGA codon. Eight genes (ND2, ATPase8, ATPase6, COIII, ND5, ND4L, ND6, and Cytb) end with a TAA stop codon, and two genes (ND1 and ND3) end with TAG. The remaining three genes (COI and COII, which end with TA-, and ND4, which ends with T-) have incomplete stop codons. All tRNAs have the typical clover-leaf structure of mitochondrial tRNAs, with the exception of tRNASer(AGY). On the basis of the concatenated nucleotide and amino acid sequences of the 13 PCGs and wingless gene of 22 butterfly species, maximum parsimony (MP) and Bayesian inference (BI) trees were constructed, respectively. Both MP and BI trees had the same topological structure: ((((Nymphalidae+ Danaidae) + Lycaenidae) + Pieridae) + Papilionidae) + Hesperiidae). The results provide support for Hesperiidae as a superfamily-level taxon.