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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
Kinesin and cytoplasmic dynein are the principal ATPase microtubule-based motors involved in organelle transport (65-68). Each type of motor associates with membranous organelles and directs movement along the length of the microtubule. Dynein drives movement toward the minus end of the microtubule, yielding a net inward flow, whereas kinesin drives movement towards the plus end, generating movement toward the cell periphery (69). Dynein is responsible for movement of endosomal and lysosomal vesicles toward the cell nucleus, while kinesin has been implicated in maintaining the extended distribution of the endoplasmic reticulum, the shape of the Golgi complex, the extension of lysosomes, and trafficking of proteins from Golgi to endoplasmic reticulum (70-72).
Mitochondrial Pathologies and Their Neuromuscular Manifestations
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Carlos Ortez, Andrés Nascimento
Early microscopic observations led to the idea that mitochondria were small, individual organelles randomly distributed within the cytoplasm. However, many teams have shown that mitochondria are highly structured, forming a complex network of interconnected tubules96,97. The mitochondrial network constitutes a dynamic system, constantly adapting to cellular requirements by changing its shape and position through processes of fission and fusion98. Indeed, the bioenergetic status of the cell is closely related to the structure of the mitochondrial network99. Insights acquired over the past decade show that mitochondrial dynamics plays a crucial role in several interdependent cellular processes such as bioenergetics, neuronal axonal transport, calcium homeostasis and apoptosis. In neurons, mitochondria are transported along the cytoskeleton of the axon, from the cell body to the periphery (anterograde transport) and from the periphery to the cell body (retrograde transport). Motor proteins of the kinesin (KIF) superfamily interact with mitochondria through the outer membrane proteins Miro1 and Miro2 and participate in anterograde transport. In contrast, cytoplasmic dynein motors mediate retrograde transport100,101. Another aspect of mitochondrial dynamics concerns fusion and fission mechanisms.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: autosomal recessive. In some patients affected by the subtype SRP3 (Verma-Naumoff), mutations in the genes IFT80 and DYNC2H1 have been found. IFT80 is a component of the anterograde intraflagellar transport (IFT) complex B and is crucial to the development and maintenance of motile and sensory cilia. DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1) encodes a subunit of a cytoplasmic dynein complex. The same genes have also been found to be mutated in ATD2 and ATD3, respectively; this finding emphasises that these conditions are part of a common clinical spectrum and are included among the ciliopathies.
Flavanol-rich lychee fruit extract substantially reduces progressive cognitive and molecular deficits in a triple-transgenic animal model of Alzheimer disease
Published in Nutritional Neuroscience, 2021
Xiao Chen, Benhong Xu, Luling Nie, Kaiwu He, Li Zhou, Xinfeng Huang, Peter Spencer, Xifei Yang, Jianjun Liu
The ER protein category included 78 kDa glucose-regulated protein (GRP 78), an ER chaperone of the HSP70 family. GRP 78 was increased in 3×Tg-AD mice and decreased in Oligonol-treated animals. Pyruvate kinase muscle (KPYM), pyruvate dehydrogenase-related (ODPA), and NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial (NDUS1) were found in the mitochondrial protein group. NDUS1, a component of mitochondrial Complex I, showed reduced expression in 3×Tg-AD mice and increased expression in Oligonol-treated animal groups. Both KPYM and OPDA participate in pyruvate metabolism. In the third category, Oligonol treatment counteracted the reduction of NDUS1 in the 3×Tg-AD group. The fourth category contained cytoplasmic dynein 1 intermediate chain 1 (DC1I1), dynamin 1, synapsin II and vimentin. Mean vimentin expression was increased in 3×Tg-AD mice and reduced in the Oligonol-treated 3×Tg-AD group. Administration of Oligonol also reduced the level of DC1I1. The synapsin II level was decreased in the 3×Tg-AD group and increased with Oligonol treatment. In summary, whereas the expression of selected proteins associated with the ER, mitochondria, proteasome, and synapse was perturbed in 3×Tg-AD mice, the perturbations were effectively reversed in animals treated with Oligonol.
Molecular mechanisms governing axonal transport: a C. elegans perspective
Published in Journal of Neurogenetics, 2020
Amruta Vasudevan, Sandhya P. Koushika
Microtubule-dependent motor proteins responsible for most fast axonal transport in neurons largely belong to the Kinesin or Dynein superfamily (Morfini et al., 2012). Kinesins are ATPases that walk towards the plus ends of microtubules in a hand-over-hand motion, with each motor head taking 16 nm steps for every molecule of ATP hydrolysed (Gennerich & Vale, 2009). Cytoplasmic dynein, a member of the AAA family of ATPases, drives transport towards the minus ends of microtubules, using an inch-worm-like movement with occasional hand-over-hand mode of stepping (Bhabha, Johnson, Schroeder, & Vale, 2016; Gennerich & Vale, 2009). Studies on intracellular transport across diverse cell types have revealed common underlying principles governing microtubule-based transport, such as i) cargo-specific mechanisms of motor recruitment and transport, ii) interactions between multiple motors on the cargo surface, and iii) navigation of the cargo-motor complex through obstacles. Several of these principles have been found to apply to axonal transport. Neurons, being polarized cells with distinct axonal and dendritic compartments, additionally exhibit region-specific regulation of cargo transport. These principles are discussed below.
Targeting central nervous system pathologies with nanomedicines
Published in Journal of Drug Targeting, 2019
Shoshy Mizrahy, Anna Gutkin, Paolo Decuzzi, Dan Peer
As described in Figure 2, pathogens do not only utilise CNS receptors for cell entry but also exploit several cellular mechanisms for CNS penetration. For example, several pathogens utilise intracellular transport, a mechanism essential for the distribution of neuronal organelles and proteins. The retrograde transport facilitated by the cytoplasmic dynein motor enables the transfer of cargo from the nerve terminus to the cell body. The use of motor based axonal transport is a key mechanism for viral spread across the CNS, especially when taking into account axon length, which makes relying on passive diffusion irrelevant [123]. The use of motor-based axonal transport following entry at peripheral nerve endings has been documented for several neurotropic viruses, bacteria and toxins including the Rabies, Poliovirus, Canine adenovirus type 2 and Tetanus toxin [123]. Therefore, it is possible that NPs conjugated with viral proteins will also be able to exploit the motor-based axonal transport for CNS spreading.