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The Journal of Neuroscience, September 27, 2006, 26(39):10006-10019; doi:10.1523/JNEUROSCI.2580-06.2006

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Neurobiology of Disease
-Internexin Is Structurally and Functionally Associated with the Neurofilament Triplet Proteins in the Mature CNS

Aidong Yuan,^1,3 Mala V. Rao,^1,3 Takahiro Sasaki,¹ Yuanxin Chen,^1,2 Asok Kumar,^1,3 Veeranna,^1,3 Ronald K. H. Liem,⁵ Joel Eyer,⁶ Alan C. Peterson,⁷ Jean-Pierre Julien,⁸ and Ralph A. Nixon^1,3,4

¹Center for Dementia Research and ²Department of Medical Physics, Nathan Kline Institute, Orangeburg, New York 10962, Departments of ³Psychiatry and ⁴Cell Biology, New York University School of Medicine, New York, New York 10016, ⁵Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, ⁶Laboratoire Neurobiologie et Transgenese, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire, 49033 Angers Cedex, France, ⁷Molecular Oncology Group, McGill University, Royal Victoria Hospital, Montreal, Québec, Canada H3A1A1, and ⁸Centre de Recherche du Centre Hospitalier de l'Université Laval, Département d'anatomie et Physiologie de l'Université Laval, Québec, Québec, Canada G1V 4G2

Correspondence should be addressed to Dr. Aidong Yuan, Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962. Email: yuan{at}nki.rfmh.org

-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 -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 -internexin and neurofilament triplet form separate filament systems. Here, we demonstrate, however, that despite a postnatal decline in expression, -internexin is as abundant as the triplet in the adult CNS and exists in a relatively fixed stoichiometry with these subunits. -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. -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 -internexin transport and content in axons throughout the CNS. Moreover, deleting -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 -internexin and neurofilament triplet to aggregate in neuronal perikarya and greatly reduces their transport and content selectively in axons. Our data show that -internexin and the neurofilament proteins are functionally interdependent. The results strongly support the view that -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.

Key words: -internexin; neurofilament; intermediate filament; neurofilament inclusion disease; tropical spastic paraparesis; axonal transport; cytoskeleton

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Received Feb. 10, 2006; revised Aug. 15, 2006; accepted Aug. 20, 2006.

Correspondence should be addressed to Dr. Aidong Yuan, Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Road, Orangeburg, NY 10962. Email: yuan{at}nki.rfmh.org

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