Intermediate filament accumulation can stabilize microtubules in<i>Caenorhabditis elegans</i>motor neurons

Kurup, N S; Li, Yunbo; Goncharov, Alexandr; Jin, Yishi

doi:10.1073/pnas.1721930115

Cited by 25 publications

(23 citation statements)

References 45 publications

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“…It has been shown recently in C . elegans that IFs hyperstabilize MTs to prevent synapse rewiring consistent with the idea that IF levels are directly associated with axonal MT stability . Importantly, organelle transport is largely affected by IFs such as vimentin in non‐neuronal cells, and in neurons the transport of NF subunits are tightly coordinated by kinesin‐1 (anterograde direction) and dynein (retrograde direction) .…”

Section: Introductionsupporting

confidence: 74%

Characterization of TAG‐63 and its role on axonal transport in C. elegans

Bhan

Shanmugam

Wang

et al. 2019

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Model organisms are increasingly used to study and understand how neurofilament (NF)-based neurological diseases develop. However, whether a NF homolog exists in C. elegans remains unclear. We characterize TAG-63 as a NF-like protein with sequence homologies to human NEFH carrying various coiled coils as well as clustered phosphorylation sites. TAG-63 also exhibits features of NFL such as a molecular weight of around 70 kD, the lack of KSP repeats and the ability to form 10 nm filamentous structures in transmission electron micrographs. An anti-NEFH antibody detects a band at the predicted molecular weight of TAG-63 in Western blots of whole worm lysates and this band cannot be detected in tag-63 knockout worms. A transcriptional tag-63 reporter expresses in a broad range of neurons, and various anti-NFH antibodies stain worm neurons with an overlapping expression of axonal vesicle transporter UNC-104(KIF1A). Cultured neurons grow shorter axons when incubating with drugs known to disintegrate the NF network and rhodaminelabeled in vitro reconstituted TAG-63 filaments disintegrate upon drug exposure. Speeds of UNC-104 motors are diminished in tag-63 mutant worms with visibly increased accumulations of motors along axons. UNC-104/TAG-63 and SNB-1/ TAG-63 not only colocalize in neurons but also revealed positive BiFC (bimolecular fluorescence assay) signals. In summary, we identified and characterized TAG-63 in C. elegans, and demonstrate that lack of this protein limits axonal transport efficiencies. Additionally, this study would aid in developing NF-related disease models in the future. K E Y W O R D S intermediate filament, kinesin-3, NEFH, neurofilament, NF, SNB-1, TAG-63, UNC-104

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Section: Introductionsupporting

confidence: 74%

Characterization of TAG‐63 and its role on axonal transport in C. elegans

Bhan

Shanmugam

Wang

et al. 2019

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“…On the other hand, the MT fragmentation along the axons could be connected to the already known action of some anti-cancer drugs, which exerted adverse effects on the peripheral nervous system in clinical studies, with documentation of degeneration and fragmentation of sensory axons, reduced axonal length and also reduced axonal transport in animal models [77]. Interestingly, it has recently been reported that intermediate filament accumulation directly alters MT stability in motor neurons in Caenorhabditis elegans [78]. Kurup and colleagues showed for the first time that the genetic loss or the pharmacological disruption of the essential intermediate filament network was sufficient to shift the MT balance from stable to dynamic, participating in the regulation of axonal transport, from which synapse rewiring depends in C. elegans.…”

Section: Discussionmentioning

confidence: 99%

The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione

Casagrande

Amadeo

Cartelli

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Exposure to environmental toxins, including hydrocarbon solvents, increases the risk of developing Parkinson's disease. An emergent hypothesis considers microtubule dysfunction as one of the crucial events in triggering neuronal degeneration in Parkinson's disease. Here, we used 2,5-hexanedione (2,5-HD), the toxic metabolite of n-hexane, to analyse the early effects of toxin-induced neurodegeneration on the cytoskeleton in multiple model systems. In PC12 cells differentiated with nerve growth factor for 5 days, we found that 2,5-HD treatment affected all the cytoskeletal components. Moreover, we observed alterations in microtubule distribution and stability, in addition to the imbalance of post-translational modifications of α-tubulin. Similar defects were also found in vivo in 2,5-HD-intoxicated mice. Interestingly, we also found that 2,5-HD exposure induced significant changes in microtubule stability in human skin fibroblasts obtained from Parkinson's disease patients harbouring mutations in PRKN gene, whereas it was ineffective in healthy donor fibroblasts, suggesting that the genetic background may really make the difference in microtubule susceptibility to this environmental Parkinson's disease-related toxin. In conclusion, by showing the imbalance between dynamic and stable microtubules in hydrocarbon-induced parkinsonism, our data support the crucial role of microtubule defects in triggering neurodegeneration.

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“…This recently developed method has been used to degrade several endogenously tagged GFP fusion proteins, revealing loss-of-function phenotypes (Chuang et al 2014;Wang et al 2017b;Kim et al 2018;Kurup et al 2018). Degradation of proteins to a level below detection can be accomplished and occurs quickly, although at least one abundantly expressed protein could not be depleted entirely using this method (Wang et al 2017b).…”

Section: Experimental Considerationsmentioning

confidence: 99%

The Caenorhabditis elegans Transgenic Toolbox

2019

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The power of any genetic model organism is, in part, derived from the ease with which gene expression can be manipulated. The short generation time and invariant developmental lineage have made Caenorhabditis elegans very useful for understanding, e.g., developmental programs, basic cell biology, neurobiology, and aging. Over the last decade, the C. elegans transgenic toolbox has expanded considerably with the addition of a variety of methods to control expression and modify genes with unprecedented resolution. Here we provide a comprehensive overview of transgenic methods in C. elegans, with an emphasis on recent advances in transposon-mediated transgenesis, CRISPR/Cas9 gene editing, conditional gene and protein inactivation, and bipartite systems for temporal and spatial control of expression.

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Intermediate filament accumulation can stabilize microtubules inCaenorhabditis elegansmotor neurons

Cited by 25 publications

References 45 publications

Characterization of TAG‐63 and its role on axonal transport in C. elegans

Characterization of TAG‐63 and its role on axonal transport in C. elegans

The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione

The Caenorhabditis elegans Transgenic Toolbox

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