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Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS.

Publication Type:

Journal Article

Source:

J Neurosci, Volume 26, Issue 39, p.10006-19 (2006)

Keywords:

Animals, Axons, Crosses, Genetic, Female, Intermediate Filament Proteins, Intermediate Filaments, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Confocal, Microscopy, Fluorescence, Microscopy, Immunoelectron, Multiprotein Complexes, Nerve Degeneration, Neurofilament Proteins, Protein Interaction Mapping, Protein Transport, Rats, Recombinant Fusion Proteins, Retinal Ganglion Cells, Spinal Cord, Structure-Activity Relationship, Transfection

Abstract:

<p>Alpha-internexin, a neuronal intermediate filament protein implicated in neurodegenerative disease, coexists with the neurofilament (NF) triplet proteins (NF-L, NF-M, and NF-H) but has an unknown function. The earlier peak expression of alpha-internexin than the triplet during brain development and its ability to form homopolymers, unlike the triplet, which are obligate heteropolymers, have supported a widely held view that alpha-internexin and neurofilament triplet form separate filament systems. Here, we demonstrate, however, that despite a postnatal decline in expression, alpha-internexin is as abundant as the triplet in the adult CNS and exists in a relatively fixed stoichiometry with these subunits. Alpha-internexin exhibits transport and turnover rates identical to those of triplet proteins in optic axons and colocalizes with NF-M on single neurofilaments by immunogold electron microscopy. Alpha-internexin also coassembles with all three neurofilament proteins into a single network of filaments in quadruple-transfected SW13vim(-) cells. Genetically deleting NF-M alone or together with NF-H in mice dramatically reduces alpha-internexin transport and content in axons throughout the CNS. Moreover, deleting alpha-internexin potentiates the effects of NF-M deletion on NF-H and NF-L transport. Finally, overexpressing a NF-H-LacZ fusion protein in mice induces alpha-internexin and neurofilament triplet to aggregate in neuronal perikarya and greatly reduces their transport and content selectively in axons. Our data show that alpha-internexin and the neurofilament proteins are functionally interdependent. The results strongly support the view that alpha-internexin is a fourth subunit of neurofilaments in the adult CNS, providing a basis for its close relationship with neurofilaments in CNS diseases associated with neurofilament accumulation.</p>

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