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A mechanism for neurofilament transport acceleration through nodes of Ranvier.

ABSTRACT: Neurofilaments are abundant space-filling cytoskeletal polymers in axons that are transported along microtubule tracks. Neurofilament transport is accelerated at nodes of Ranvier, where axons are locally constricted. Strikingly, these constrictions are accompanied by sharp decreases in neurofilament number, no decreases in microtubule number, and increases in the packing density of these polymers, which collectively bring nodal neurofilaments closer to their microtubule tracks. We hypothesize that this leads to an increase in the proportion of time that the filaments spend moving and that this can explain the local acceleration. To test this, we developed a stochastic model of neurofilament transport that tracks their number, kinetic state, and proximity to nearby microtubules in space and time. The model assumes that the probability of a neurofilament moving is dependent on its distance from the nearest available microtubule track. Taking into account experimentally reported numbers and densities for neurofilaments and microtubules in nodes and internodes, we show that the model is sufficient to explain the local acceleration of neurofilaments within nodes of Ranvier. This suggests that proximity to microtubule tracks may be a key regulator of neurofilament transport in axons, which has implications for the mechanism of neurofilament accumulation in development and disease.

SUBMITTER: Ciocanel MV

PROVIDER: S-EPMC7202067 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A mechanism for neurofilament transport acceleration through nodes of Ranvier.

Ciocanel Maria-Veronica MV Jung Peter P Brown Anthony A

Molecular biology of the cell 20200205 7

Neurofilaments are abundant space-filling cytoskeletal polymers in axons that are transported along microtubule tracks. Neurofilament transport is accelerated at nodes of Ranvier, where axons are locally constricted. Strikingly, these constrictions are accompanied by sharp decreases in neurofilament number, no decreases in microtubule number, and increases in the packing density of these polymers, which collectively bring nodal neurofilaments closer to their microtubule tracks. We hypothesize th ...[more]

PMID: 32023144

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Project description:Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP) and chronic idiopathic axonal polyneuropathies (CIAP). The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70 ± 4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP and the alterations in paranodin immunofluorescence may be an interesting tool for their differential diagnosis.

Dataset Information

A mechanism for neurofilament transport acceleration through nodes of Ranvier.

Publications

A mechanism for neurofilament transport acceleration through nodes of Ranvier.

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