Neuropathology: Many Paths Lead toHereditary Spastic Paraplegia

Robert M. Gould and Scott T. Brady

Studies with animal models are providing newinsights into the pathology of hereditary spasticparaplegia, particularly how mutations in multiple,converging pathways can lead to this family ofneuropathies.

Diseases of the nervous system — neuropathies —are diagnosed on the basis of criteria that include theaffected nerve populations, age of onset andpathological hallmarks. Hereditary spastic paraplegia(HSP) is characterized by progressive spasticity andmild weakness in the lower limbs, in some casesaccompanied by additional neurological symptomsincluding mental retardation and optic neuropathy [1].Typically, the longest nerve fibers — those innervatingthe lower extremities — are the earliest to be affected,and these exhibit a dying back neuropathy in whichdamage to terminal and preterminal regions precedechanges in cell bodies. This led to suggestions thataxonal transport might be specifically affected in HSP,an idea that was reinforced by the discovery that akinesin heavy chain mutation is responsible for somecases of HSP [2]. But the family of HSP diseases maybe caused by defects in any one of over 20 genes,some of which are expressed in neurons whereasothers are only in myelinating glial cells [1,3]. In recentmonths, three papers [4–6] have reported the use ofanimal models of HSP to provide new evidencesuggesting that many of the various mutations inaxonal and glial cell proteins may lead to HSP throughconvergent pathways.

Two of these papers [4,5] looked at axonal andsynaptic changes in response to the expression ofmutant proteins by myelinating glia. Yin et al. [4] reportthe changes in synaptic terminal structure andfunction that result when axons are myelinated by gliaoverexpressing protein 0 (P0), the dominant protein ofperipheral nerve myelin. P0 overexpression preventsproper targeting of other myelin-related proteins,resulting in an overabundance of Schwann cells and afailure to generate myelinated internodes. Althoughthis Schwann cell abnormality does not appear toaffect axon maturation in terms of axon caliber andinitial muscular innervation, it causes problems in theability of neurons to maintain their terminal connec-tions with muscle. Yin et al. [4] stress the importanceof synaptic degeneration preceding axonal degenera-tion — ‘dying back’ neuropathy — but they fail toexplain why the terminals, which appear to form nor-mally, are not maintained. They do, however, suggest

that some, as yet unidentified, molecules that areneeded to maintain the terminals are not transportedefficiently with this form of dysmyelination.

Edgar et al. [5] examined an animal model of HSPwith a defect in another myelin protein, PLP.Mutations of PLP can cause HSP in humans [3] and inanimal models [7]. What they observed was the accu-mulation of retrogradely transported organelles,mainly in distal portions of axoplasm underlying nodesof Ranvier adjacent to abnormal myelin sheaths. Theaccumulations occurred in nerves from PLP null mice,in which all myelin lacks PLP; they were also observedin the limited number of myelin segments formedwhen glia from PLP null mice were transplanted intothe spinal cords of shiverer mutant mice, whichnormally lack myelin basic protein and myelin sheaths.The transplanted mutant glia form patches of myelinthat lacks PLP and vesicle accumulations were seenonly in axon segments surrounded by mutant myelin.

These results suggested a specific local effect ofthe myelin sheath on retrograde axonal transport.Consistent with this, Edgar et al. [5] found that theaccumulation of a tracer, fluorescent cholera toxin, inretinal ganglion cell bodies after injection into thesuperior colliculus was diminished in PLP null mice. Adefect in retrograde signaling had previously beensuggested to underlie some forms of HSP, givenindications that abnormal endosome function isassociated with this neuropathy [8–11]. The mecha-nism by which changes in a myelin sheath could affectretrograde axonal transport remains to be determined,but previous studies [12,13] had demonstrated thatchanges in axonal signaling are associated with myeli-nation. Myelin sheaths were found to have both localeffects on axonal kinases and phosphatases, as wellas altering retrograde signaling [12] and neuronal geneexpression [13].

In the third paper, published recently in CurrentBiology, Trotta et al. [6] examined the effect ofchanging expression levels of D-spastin — the humanhomolog of which is linked to 40% of HSP cases — onsynaptic terminal stability and function in Drosophila.Using genetics and RNA interference (RNAi) methods,the authors either overexpressed or underexpressedD-spastin — 60% similar in sequence to mammalianspastin — selectively in the Drosophila nervoussystem and muscle. Presumably through interactionswith microtubules, D-spastin influences synapticproperties at the Drosophila neuromuscular junction.Overexpression of neuronal D-spastin caused under-growth of synaptic terminals and diminished activity;in contrast, reduction of D-spastin by RNAi increasedsynaptic activity.

Spastin is known to affect microtubule dynamics inmammals [14], so Trotta et al. [6] examined howvarying the D-spastin level affects microtubuledynamics in Drosophila neurons by measuringchanges in tubulin acetylation, a common marker for

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Current Biology, Vol. 14, R903–R904, October 26, 2004, ©2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.cub.2004.09.076

Department of Anatomy and Cell Biology, University of Illinoisat Chicago, Chicago, Illinois 60612, USA. E-mail: stbrady@uic.edu

microtubule dynamics. As predicted, overexpressionof D-spastin decreased tubulin acetylation levels, anddownregulation of D-spastin had the opposite effect.Complementary effects on Drosophila synaptic func-tion were seen with agents that either stabilize (taxol)or destabilize (nocodazole) microtubules. Remarkably,changes in myelination of mammalian nerves can alsoalter microtubule dynamics [15,16]. Again the specificpathways that connect changing microtubule dynam-ics and synaptic function is unclear, though agentsthat affect microtubule dynamics have long beenknown to affect fast axonal transport and spastin mayinfluence the delivery and/or removal of synaptic pro-teins via an effect on transport.

Changes in the anterograde or retrograde transportof vesicles continue to be implicated in the pathogen-esis of dying back neuropathies. Consistent with sucha mechanism are reports that mutations in kinesinheavy chain isoforms are responsible for some formsof both HSP [2] and Charcot-Marie-Tooth type 2a [17].Similarly, dynein heavy chain mutations can producespinal muscular atrophy [18]. The challenge has beento understand how 20 genes implicated in HSP couldproduce a similar spectrum of pathological changes.This was particularly challenging for genes expressedonly in myelin. The latest findings [4–6] indicate thereare connections between myelinating glia and vesicletransport in axons. Once axons begin to interact withmyelinating glial cells, glia begin influencing bothvesicle transport in the axon and retrograde signalingin the neuron. Changes in vesicle transport, and con-sequent changes in retrograde signaling, in turn affectthe ability of a neuron to maintain functional connec-tions with its targets. Alterations in these pathways,whether due to changes in motors, the cytoskeletonor the pathways regulating them, can produce synap-tic degeneration and the dying back neuropathy char-acteristic of HSP.

References1. Crosby, A.H., and Proukakis, C. (2002). Is the transportation

highway the right road for hereditary spastic paraplegia? Am. J.Hum. Genet. 71, 1009-1016.

2. Reid, E., Kloos, M., Ashley-Koch, A., Hughes, L., Bevan, S.,Svenson, I.K., Graham, F.L., Gaskell, P.C., Dearlove, A., Pericak-Vance, M.A., et al. (2002). A kinesin keavy chain (KIF5A) mutation inhereditary spastic paraplegia (SPG10). Am. J. Hum. Genet. 71,1189-1194.

3. Reid, E. (2003). Science in motion: common molecular pathologicalthemes emerge in the hereditary spastic paraplegias. J. Med.Genet. 40, 81-86.

4. Yin, X., Kidd, G.J., Pioro, E.P., McDonough, J., Dutta, R., Feltri, M.L.,Wrabetz, L., Messing, A., Wyatt, R.M., Balice-Gordon, R.J., andTrapp, B.D. (2004). Dysmyelinated lower motor neurons retract andregenerate dysfunctional synaptic terminals. J. Neurosci. 24, 3890-3898.

5. Edgar, J.M., McLaughlin, M., Yool, D., Zhang, S.C., Fowler, J.H.,Montague, P., Barrie, J.A., McCulloch, M.C., Duncan, I.D., Garbern,J., et al. (2004). Oligodendroglial modulation of fast axonal transportin a mouse model of hereditary spastic paraplegia. J. Cell. Biol. 166,121-131.

6. Trotta, N., Orso, G., Rossetto, M.G., Daga, A., and Broadie, K.(2004). The hereditary spastic paraplegia gene, spastin, regulatesmicrotubule stability to modulate synaptic structure and function.Curr. Biol. 14, 1135-1147.

7. Griffiths, I., Klugmann, M., Anderson, T., Yool, D., Thomson, C.,Schwab, M.H., Schneider, A., Zimmermann, F., McCulloch, M.,Nadon, N., and Nave, K.A. (1998). Axonal swellings and degenera-tion in mice lacking the major proteolipid of myelin. Science 280,1610-1613.

8. Zhao, X., Alvarado, D., Rainier, S., Lemons, R., Hedera, P., Weber,C.H., Tukel, T., Apak, M., Heiman-Patterson, T., Ming, L., et al.(2001). Mutations in a newly identified GTPase gene cause autoso-mal dominant hereditary spastic paraplegia. Nat. Genet. 29, 326-331.

9. Patel, H., Cross, H., Proukakis, C., Hershberger, R., Bork, P.,Ciccarelli, F.D., Patton, M.A., McKusick, V.A., and Crosby, A.H.(2002). SPG20 is mutated in Troyer syndrome, an hereditary spasticparaplegia. Nat. Genet. 31, 347-348.

10. Verhoeven, K., De Jonghe, P., Coen, K., Verpoorten, N., Auer-Grumbach, M., Kwon, J.M., FitzPatrick, D., Schmedding, E., DeVriendt, E., Jacobs, A., et al. (2003). Mutations in the small GTP-aselate endosomal protein RAB7 cause Charcot-Marie-Tooth type 2Bneuropathy. Am. J. Hum. Genet. 72, 722-727.

11. Yamanaka, K., Vande Velde, C., Eymard-Pierre, E., Bertini, E.,Boespflug-Tanguy, O., and Cleveland, D.W. (2003). Unstablemutants in the peripheral endosomal membrane component ALS2cause early-onset motor neuron disease. Proc. Natl. Acad. Sci. USA100, 16041-16046.

12. de Waegh, S.M., Lee, V.M.-Y., and Brady, S.T. (1992). Local modu-lation of neurofilament phosphorylation, axonal caliber, and slowaxonal transport by myelinating Schwann cells. Cell 68, 451-463.

13. Brady, S.T., Witt, A.S., Kirkpatrick, L.L., de Waegh, S.M., Readhead,C., Tu, P.-H., and Lee, V.M.-Y. (1999). Formation of compact myelinis required for maturation of the axonal cytoskeleton. J. Neurosci.19, 7278-7288.

14. Errico, A., Ballabio, A., and Rugarli, E.I. (2002). Spastin, the proteinmutated in autosomal dominant hereditary spastic paraplegia, isinvolved in microtubule dynamics. Hum. Mol. Genet. 11, 153-163.

15. Kirkpatrick, L.L., and Brady, S.T. (1994). Modulation of the axonalmicrotubule cytoskeleton by myelinating Schwann cells. J.Neurosci. 14, 7440-7450.

16. Kirkpatrick, L.L., Witt, A.S., Payne, H.R., Shine, H.D., and Brady, S.T.(2001). Changes in microtubule stability and density in myelin-defi-cient shiverer mouse CNS axons. J. Neurosci. 21, 2288-2297.

17. Zhao, C., Takita, J., Tanaka, Y., Setou, M., Nakagawa, T., Takeda,S., Yang, H.W., Terada, S., Nakata, T., Takei, Y., et al. (2001).Charcot-Marie-Tooth disease type 2A caused by mutation in amicrotubule motor KIF1Bbeta. Cell 105, 587-597.

18. Hafezparast, M., Klocke, R., Ruhrberg, C., Marquardt, A., Ahmad-Annuar, A., Bowen, S., Lalli, G., Witherden, A.S., Hummerich, H.,Nicholson, S., et al. (2003). Mutations in dynein link motor neurondegeneration to defects in retrograde transport. Science 300, 808-812.

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