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Published online 28 June 2004. doi:10.1083/jcb.200312012
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 1, 121-131
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Article

Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia



Julia M. Edgar1, Mark McLaughlin1, Donald Yool1, Su-Chun Zhang3, Jill H. Fowler2, Paul Montague1, Jennifer A. Barrie1, Mailis C. McCulloch1, Ian D. Duncan3, James Garbern4, Klaus A. Nave5, and Ian R. Griffiths1

1 Applied Neurobiology Group, Institute of Comparative Medicine
2 Clinical Neuroscience, Wellcome Surgical Institute, University of Glasgow, Glasgow G61 1QH, Scotland, UK
3 Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706
4 Department of Neurology and Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201
5 Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany

Address correspondence to I.R. Griffiths, Applied Neurobiology Group, Dept. of Veterinary Clinical Studies, University of Glasgow, Bearsden, Glasgow G61 1QH, Scotland, UK. Tel.: 0141-330-5806. Fax: 0141-942-7215. email: I.Griffiths{at}vet.gla.ac.uk


Abstract

Oligodendrocytes are critical for the development of the plasma membrane and cytoskeleton of the axon. In this paper, we show that fast axonal transport is also dependent on the oligodendrocyte. Using a mouse model of hereditary spastic paraplegia type 2 due to a null mutation of the myelin Plp gene, we find a progressive impairment in fast retrograde and anterograde transport. Increased levels of retrograde motor protein subunits are associated with accumulation of membranous organelles distal to nodal complexes. Using cell transplantation, we show categorically that the axonal phenotype is related to the presence of the overlying Plp null myelin. Our data demonstrate a novel role for oligodendrocytes in the local regulation of axonal function and have implications for the axonal loss associated with secondary progressive multiple sclerosis.

Key Words: proteolipid protein; oligodendrocyte; axonal transport; hereditary spastic paraplegia; axonal degeneration

The online version of this article includes supplemental material.

D. Yool's present address is Dept. of Veterinary Clinical Studies, Royal (Dick) School of Veterinary Studies, Hospital for Small Animals, Easter Bush Veterinary Centre, Roslin EH25 9RG, Scotland, UK.

Abbreviations used in this paper: CTB, cholera toxin B subunit; HSP, hereditary spastic paraplegia; MBP, myelin basic protein; NF, neurofilament; PLP, proteolipid protein; RGC, retinal ganglion cell.


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