Neurofilament heavy chain side arm phosphorylation regulates axonal transport of neurofilaments

doi:10.1083/jcb.200303138

Published 12 May 2003. doi:10.1083/jcb.200303138

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© The Rockefeller University Press, 0021-9525/2003/5/489 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 489-495

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Neurofilament heavy chain side arm phosphorylation regulates axonal transport of neurofilaments

Steven Ackerley, Paul Thornhill, Andrew J. Grierson, Janet Brownlees, Brian H. Anderton, P. Nigel Leigh, Christopher E. Shaw and Christopher C.J. Miller

Departments of Neuroscience and Neurology, The Institute of Psychiatry, Kings College London, London SE5 8AF, UK

Address correspondence to Christopher C.J. Miller, Department of Neuroscience, P.O. Box PO37, The Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK. Tel.: 44-207-848-0393. Fax: 44-207-708-0017. E-mail: chris.miller{at}iop.kcl.ac.uk

Neurofilaments possess side arms that comprise the carboxy-terminaldomains of neurofilament middle and heavy chains (NFM and NFH);that of NFH is heavily phosphorylated in axons. Here, we demonstratethat phosphorylation of NFH side arms is a mechanism for regulatingtransport of neurofilaments through axons. Mutants in whichknown NFH phosphorylation sites were mutated to preclude phosphorylationor mimic permanent phosphorylation display altered rates oftransport in a bulk transport assay. Similarly, applicationof roscovitine, an inhibitor of the NFH side arm kinase Cdk5/p35,accelerates neurofilament transport. Analyses of neurofilamentmovement in transfected living neurons demonstrated that a mutantmimicking permanent phosphorylation spent a higher proportionof time pausing than one that could not be phosphorylated. Thus,phosphorylation of NFH slows neurofilament transport, and thisis due to increased pausing in neurofilament movement.

Key Words: neurofilament proteins; axonal transport; amyotrophic lateral sclerosis; Alzheimer's disease; Cdk5/p35

S. Ackerley, P. Thornhill, and A.J. Grierson contributed equallyto this work.

^* Abbreviations used in this paper: NFH, neurofilament heavy chain;NFL, neurofilament light chain; NFM, neurofilament middle chain;scg, superior cervical ganglion.

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