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Manipulating the Intracellular Trafficking of Nucleic Acids
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Kathleen E. B Meyer, Lisa S. Uyechi, Francis C. Szoka
The motor proteins are believed to attach to receptor proteins anchored in organelle membranes, and two such receptor proteins have been identified and are currently under investigation (73). The kinectin protein is thought to join kinesin to the organelle membrane. Kinectin is predicted by its amino acid sequence to form a coiled-coil motif and is anchored in the membrane by its N-terminal sequence (74). Antibodies to kinectin, blocking potential binding sites for kinesin, inhibit plus-end-directed organelle movement in vitro by 90% (75). The dynactin complex, consisting of 10 different polypeptides, is capable of interacting with cytoplasmin dynein as well as microtubules, kinetochores, and membranes (73), yet the molecular events involved in attachment have not been elucidated. The interaction of microtubules with membranous organelles also appears to involve linker protein, or CLIPS, that bind to membranes via protein receptors (73,76). It remains to be determined whether additional kinectin- or dynactinlike proteins exist, which receptor proteins are found on specific organelles, and how organelle movement is orchestrated.
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
Microtubules act as tracks for cargo transport with the help of motor proteins (kinesin and dynein) in and out of the cells. The motor proteins kinesin and dynein associate with cargoes and transport them along microtubules. Tubulin posttranslational modifications are associated with the recruitment of specific types of motor molecules. For example, acetylated α-tubulin specifically interacts with kinesin 1 cargo complex, whereas tyrosinated α-tubulin interacts with kinesin 3 cargo complex [65]. Assuming from the fact that pharmacologic ascorbate enhanced α-tubulin acetylation, it is possible that cargo transport is influenced. Currently, there efforts have not been made to understand the effect of ascorbate on cargo transport mediated by motor proteins. This question is particularly important in neuronal transport, that ascorbate might have pathophysiologic or therapeutic implication for diseases of the nervous system. Microtubules in the axon organize into bundles and enable efficient transport of neurotransmitters. Such bundled microtubules are also observed in primary cilia and flagella, as well as in mitotic spindles. Often, these microtubules are marked by acetylation. Further research is required to address these intriguing questions.
What role for genetic testing in sport?
Published in Silvia Camporesi, Mike McNamee, Bioethics, Genetics and Sport, 2018
Silvia Camporesi, Mike McNamee
Over the past 30 years genetic scientists have not made much progress concerning precisely what genes are involved in response to training. This should not be surprising as trainability is a complex trait. What we know thanks to genome-wide linkage studies (GWLS) is that there are two loci, respectively one on chromosome 10p11 and one on chromosome 2q33.3-q34, that have been linked to training-induced changes in submaximal exercise. Some of the candidate genes belong to members of the kinesin family (which makes sense, as kinesins are motor protein involved in cellular transport, including the transport of chromosomes during mitosis and meiosis, neurotransmitters and other important ‘molecular cargo’: Argyropoulos et al. 2009). To conclude, we know that there is a genetic component to trainability but we do not know what genes are involved. Currently GWAS studies are under way (Ghosh et al. 2013). Other questions remain open, such as whether the response pattern in a given individual is specific to the given exercise mode and regimen, and whether the duration of the exercise intervention or training programme also makes a difference. It is plausible to speculate that there is a highly contextual response and that many genes are involved in trainability. For the moment it is impossible to predict from having certain allelic variations that somebody will a better response to an intervention.
Misconnecting the dots: altered mitochondrial protein-protein interactions and their role in neurodegenerative disorders
Published in Expert Review of Proteomics, 2020
Mara Zilocchi, Mohamed Taha Moutaoufik, Matthew Jessulat, Sadhna Phanse, Khaled A. Aly, Mohan Babu
Additionally, overexpression or mutations in α-Syn impact mt fragmentation as observed in several cell lines and human samples, revealing a role for altered α-Syn in impaired mt dynamics observed in PD [152–154]. α-Syn aggregation is also observed in PD, which impairs the anterograde-to-retrograde mt flux and causes transport defects [152,155]. Indeed, this PD-related protein interacts with the molecular motor machinery and disrupts the association of kinesin-1 motors and microtubules, damaging the transport of mt and other neuronal cargo mechanisms [156,157]. Similar to α-Syn, mutations in CHCHD2 (coiled-coil-helix-coiled-coil-helix domain containing 2) cause the onset of autosomal dominant PD due to impaired energy metabolism [158]. Under physiological conditions, CHCHD2 directly binds to mt complex IV subunits (cytochrome c oxidase, a respiratory chain complex) and this interaction is necessary for complex IV activity [159]. Accordingly, CHCHD2 knockdown cells show reduction in the levels of both, complex I and IV [159,160], alterations in mt morphology, impaired oxygen respiration, loss of dopaminergic neurons, and motor deficits in Drosophila, similar to PD-associated symptoms, revealing a role for altered CHCHD2 in rewiring of mtPPIs in PD with notable impairment in energy metabolism [158].
TDZD-8 alleviates delayed neurological sequelae following acute carbon monoxide poisoning involving tau protein phosphorylation
Published in Inhalation Toxicology, 2020
Chenglei Su, Ningjun Zhao, Jianjiao Zou, Xianliang Yan
GSK-3β is thought play a critical role in Tau phosphorylation (Dey et al. 2017). The hyperphosphorylation of Tau is considered to impair cognitive function (Wang and Mandelkow 2016), as phosphorylation is increased in many neurodegenerative diseases, such as AD or ischemic neurological deficit (Mukrasch et al. 2009; Pluta et al. 2018). Hyperphosphorylation of Tau might induce synaptic dysfunction (Thies and Mandelkow 2007; Hoover et al. 2010) and enhance tau aggregation. What’s more, hyperphosphorylation of tau might lead to abnormal accumulation of F-actin filaments (Fulga et al. 2007) and impairment of kinesin complex (Fulga et al. 2007). Our results confirmed that the protein level of phosphorylation of Tau significantly increased in rat brain after CO exposure. TDZD-8 treatment decreased the hyperphosphorylation of Tau induced by CO poisoning. It is suggested that Tau was involved in the mechanisms of TDZD-8 neuroprotection.
SNP rs10800708 within the KIF14 miRNA binding site is linked with breast cancer
Published in British Journal of Biomedical Science, 2019
A Shasttiri, M Rostamian Delavar, M Baghi, M Dehghani Ashkezari, K Ghaedi
Breast cancer is one of the most frequent malignancies diagnosed in females and one of most common types of neoplasia among all cancers worldwide: its development is the outcome of intricate interactions between the environment and the genome [1–3]. Common variants in low penetrance genes accompanied by lifestyle and environmental factors play key roles in aetiology [4]. Kinesin family member 14 (KIF14) is a motor protein implicated in chromosome segregation, bipolarity regulation, mitotic cell division and cytokinesis [5]. Its expression has been clinically linked with increased breast cancer mortality and invasiveness. Combined data from several studies suggest that KIF14 can play a profound role in oncogenesis, may act as a prognostic factor, and could be a therapeutic target [5–7]. Single nucleotide polymorphisms (SNPs) are the most frequent type of germline variations, and candidate SNPs support the development of multigenic disease models that predict the consequence of a disease [8]. Genome-wide association studies have recognized a relationship between many SNPs, functioning as common low-penetrance variant alleles, and breast cancer in women [1,2,9,10].