Molecular mechanisms for organizing the neuronal cytoskeleton

Mukhopadhyay, Rajendrani; Kumar, Sanjay; Hoh, Jan H.

doi:10.1002/bies.20088

Cited by 74 publications

(76 citation statements)

References 84 publications

(86 reference statements)

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“…The structural integrity of neuronal processes (axons and dendrites) is important for neurotransmission, thus maintaining optimal neuronal function (17). Our study shows that infection with pathogenic, but not attenuated, RV induces degeneration and destruction of neuronal processes under both in vivo and in vitro conditions.…”

mentioning

confidence: 66%

Degeneration of Neuronal Processes after Infection with Pathogenic, but Not Attenuated, Rabies Viruses

Li¹,

Sarmento²,

2005

J Virol

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The structural alterations of neuronal processes in mice were investigated after the mice were infected with rabies virus (RV). Silver staining of infected brain sections showed severe destruction and disorganization of neuronal processes in mice infected with pathogenic RV but not with attenuated RV. However, neuronal bodies showed very little pathological changes. Electron microscopy revealed the disappearance of intracellular organelles, as well as the disappearance of synaptic structures and vesicles. Infection of primary neurons with pathogenic, but not attenuated, RV resulted in the destruction of neuronal processes and disappearance of microtubule-associated protein 2 and neurofilament immunoreactivity, which suggests that pathogenic RV causes degeneration of neuronal processes possibly by interrupting cytoskeletal integrity.Despite extensive investigation, the mechanism by which rabies virus (RV) infection causes neurological disease and death is still not completely understood (3). RV enters the peripheral nervous system at the bite site by binding to one or more specific neural receptors (14,22,25) with or without local replication (19,21). Once inside neurons, RV is spread by retrograde transport to the spinal cord and then to the brain (4, 12). Clinical signs include severe agitation, depression, hydrophobia, and paralysis followed by impaired consciousness and coma (9). Patients eventually die of circulatory insufficiency, cardiac arrest, and respiratory failure (9, 23). Despite the dramatic and severe clinical course, postmortem examination of rabies patients reveals only a few pathological lesions, such as cerebral edema (18). Inflammatory reactions and other histological lesions are mild with relatively little neuronal loss (15, 18). These observations led to the hypothesis that fatal rabies may result from neuronal dysfunction rather than neuronal damage (24).Studies of neuronal dysfunction have revealed electroencephalographic abnormalities, including the disappearance of rapid eye movement sleep and the development of pseudoperiodic facial myoclonus (6). Brain electrical activity terminated about 30 min before cardiac arrest, indicating that cerebral death in experimental rabies occurs prior to failure of vegetative functions (6, 7). RV infection of neurons also induces dysfunction of ion channels, for example, reduction in sodium channels and inward rectifier potassium channels (10, 11), which could prevent infected neurons from firing action potentials and generating synaptic potentials, resulting in functional impairment. Decreased binding of serotonin (particularly the subtype 5-HT 1D ) to its receptors has also been reported (2). Recent studies of the release of norepinephrine, dopamine, and serotonin in the hippocampi of rats infected with RV indicated that at the terminal stage of the disease, neurons are no longer capable of releasing neurotransmitters at the synaptic junctions (5). Hence, there is evidence of impaired release of neurotransmitters and binding of neurotransmitters to th...

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mentioning

confidence: 66%

Degeneration of Neuronal Processes after Infection with Pathogenic, but Not Attenuated, Rabies Viruses

Li¹,

Sarmento²,

2005

J Virol

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“…On the other hand steric constraints between MT-MAPs are responsible for repulsive forces between MTs [340]. The hydrophobic part is very flexible and can be described in terms of a polymer brush model [264]. The interdistance between MTs in the axon is directly related to the effective length of tau proteins [72,129].…”

Section: Modification Of Mts By Maps : the Example Of Tau Proteinsmentioning

confidence: 99%

“…For example, highly phosphorylated tau or MAP2 proteins are more rigid. Then, as a consequence of higher repulsive forces, the interdistance between MTs is increased both in axons and dendrites [264], a feature which can even result in dendritic branching [130]. It is also known that phosphorylation of tau may reduce its affinity to MTs [101,102].…”

Section: Modification Of Mts By Maps : the Example Of Tau Proteinsmentioning

confidence: 99%

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

2015

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Cells are the elementary units of living organisms, which are able to carry out many vital functions. These functions rely on active processes on a microscopic scale. Therefore, they are strongly out-of-equilibrium systems, which are driven by continuous energy supply. The tasks that have to be performed in order to maintain the cell alive require transportation of various ingredients, some being small, others being large. Intracellular transport processes are able to induce concentration gradients and to carry objects to specific targets. These processes cannot be carried out only by diffusion, as cells may be crowded, and quite elongated on molecular scales. Therefore active transport has to be organized.The cytoskeleton, which is composed of three types of filaments (microtubules, actin and intermediate filaments), determines the shape of the cell, and plays a role in cell motion. It also serves as a road network for a special kind of vehicles, namely the cytoskeletal motors. These molecules can attach to a cytoskeletal filament, perform directed motion, possibly carrying along some cargo, and then detach.It is a central issue to understand how intracellular transport driven by molecular motors is regulated. The interest for this type of question was enhanced when it was discovered that intracellular transport breakdown is one of the signatures of some neuronal diseases like the Alzheimer.We give a survey of the current knowledge on microtubule based intracellular transport. Our review includes on the one hand an overview of biological facts, obtained from experiments, and on the other hand a presentation of some modeling attempts based on cellular automata. We present some background knowledge on the original and variants of the TASEP (Totally Asymmetric Simple Exclusion Process), before turning to more application oriented models. After addressing microtubule based transport in general, with a focus on in vitro experiments, and on cooperative effects in the transportation of large cargos by multiple motors, we concentrate on axonal transport, because of its relevance for neuronal diseases. Some important characteristics of axonal transport is that it takes place in a confined environment; Besides several types of motors are involved, that move in opposite directions. It is a challenge to understand how this bidirectional transport is organized. We review several features that could contribute to the efficiency of bidirectional transport in the axon, including in particular the role of motor-motor interactions and of the dynamics of the underlying microtubule network. Finally, we also discuss some open questions that may be relevant for future research in this field.

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“…The induction of folding by binding partner molecules is a common theme (8,9,12) and allows the structure-function paradigm to be extended to many IDPs, although a degree of disorder is often maintained in the bound state, a concept known as fuzziness (12). Nonetheless, some disordered domains exert their function in the unstructured state (7,13) as entropic chains: e.g., the MAP2 projection domain that governs spacing of microtubules in the cytoplasm (14). IDPs with a protein stabilization function might behave similarly: LEA proteins reduce the formation of aggregates in a wide variety of other polypeptides subjected to environmental stress (desiccation, freezing, or heat) (15)(16)(17) or in aggregationprone proteins containing expanded stretches of polyglutamine or polyalanine (15).…”

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confidence: 99%

Catalytic and chaperone-like functions in an intrinsically disordered protein associated with desiccation tolerance

Chakrabortee

Meersman

Schierle

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered proteins (IDPs) lack well-defined structure but are widely represented in eukaryotic proteomes. Although the functions of most IDPs are not understood, some have been shown to have molecular recognition and/or regulatory roles where their disordered nature might be advantageous. Anhydrin is an uncharacterized IDP induced by dehydration in an anhydrobiotic nematode, Aphelenchus avenae. We show here that anhydrin is a moonlighting protein with two novel, independent functions relating to desiccation tolerance. First, it has a chaperone-like activity that can reduce desiccation-induced enzyme aggregation and inactivation in vitro. When expressed in a human cell line, anhydrin localizes to the nucleus and reduces the propensity of a polyalanine expansion protein associated with oculopharyngeal muscular dystrophy to form aggregates. This in vivo activity is distinguished by a loose association of anhydrin with its client protein, consistent with a role as a molecular shield. In addition, anhydrin exhibits a second function as an endonuclease whose substrates include supercoiled, linear, and chromatin linker DNA. This nuclease activity could be involved in either repair of desiccation-induced DNA damage incurred during anhydrobiosis or in apoptotic or necrotic processes, for example, but it is particularly unexpected for anhydrin because IDP functions defined to date anticorrelate with enzyme activity. Enzymes usually require precise three-dimensional positioning of residues at the active site, but our results suggest this need not be the case. Anhydrin therefore extends the range of IDP functional categories to include catalysis and highlights the potential for the discovery of new functions in disordered proteomes.anhydrobiosis | endonuclease | intrinsically unstructured protein | molecular shield | natively unfolded protein

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Molecular mechanisms for organizing the neuronal cytoskeleton

Cited by 74 publications

References 84 publications

Degeneration of Neuronal Processes after Infection with Pathogenic, but Not Attenuated, Rabies Viruses

Degeneration of Neuronal Processes after Infection with Pathogenic, but Not Attenuated, Rabies Viruses

Intracellular transport driven by cytoskeletal motors: General mechanisms and defects

Catalytic and chaperone-like functions in an intrinsically disordered protein associated with desiccation tolerance

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