Acta Neuropathologica

, Volume 109, Issue 1, pp 5–13 | Cite as

Axonal transport defects: a common theme in neurodegenerative diseases

  • Subhojit Roy
  • Bin Zhang
  • Virginia M.-Y. Lee
  • John Q. Trojanowski
Review

Abstract

A core pathology central to most neurodegenerative diseases is the misfolding, fibrillization and aggregation of disease proteins to form the hallmark lesions of specific disorders. The mechanisms underlying these brain-specific neurodegenerative amyloidoses are the focus of intense investigation and defective axonal transport has been hypothesized to play a mechanistic role in several neurodegenerative disorders; however, this hypothesis has not been extensively examined. Discoveries of mutations in human genes encoding motor proteins responsible for axonal transport do provide direct evidence for the involvement of axonal transport in neurodegenerative diseases, and this evidence is supported by studies of animal models of neurodegeneration. In this review, we summarize recent findings related to axonal transport and neurodegeneration. Focusing on specific neurodegenerative diseases from a neuropathologic perspective, we highlight discoveries of human motor protein mutations in some of these diseases, as well as illustrate new insights from animal models of neurodegenerative disorders. We also review the current understanding of the biology of axonal transport including major recent findings related to slow axonal transport.

Keywords

Axonal transport Alzheimer’s disease Frontotemporal dementias Parkinson’s disease Polyglutamine diseases 

References

  1. 1.
    Baas PW (2002) Microtubule transport in the axon. Int Rev Cytol 212:41–62PubMedGoogle Scholar
  2. 2.
    Baas PW, Brown A (1997) Slow axonal transport: the polymer transport model. Trends Cell Biol 7:380–384CrossRefGoogle Scholar
  3. 3.
    Ben Othmane KB, Middleton LT, Loprest LJ, Wilkinson KM, Lennon F, Rozear MP, Stajich JM, Gaskell PC, Roses AD, Pericak-Vance MA, Vance JM (1993) Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics 17:370–375CrossRefPubMedGoogle Scholar
  4. 4.
    Benstead TJ, Grant IA (2001) Progress in clinical neurosciences: Charcot-Marie- Tooth disease and related inherited peripheral neuropathies. Can J Neurol Sci 28:199–214PubMedGoogle Scholar
  5. 5.
    Brown A (2003) Axonal transport of membranous and nonmembranous cargoes: a unified perspective J Cell Biol 160:817–821 (See also the animation of axonal transport that accompanies this paper at http://www.jcb.org/cgi/content/full/jcb.200212017/DC1)Google Scholar
  6. 6.
    Deacon SW, Serpinskaya AS, Vaughan PS, Fanarraga ML, Vernos I, Vaughan KT, Gelfand VI (2003) Dynactin is required for bidirectional organelle transport. J Cell Biol 160:297–301CrossRefPubMedGoogle Scholar
  7. 7.
    Duda JE, Giasson BI, Mabon M, Lee VM-Y, Trojanowski JQ (2002) Novel antibodies to oxidized alpha-synuclein reveal abundant neuritic pathology in Lewy body diseases. Ann Neurol 52:205–210CrossRefPubMedGoogle Scholar
  8. 8.
    Ferreira A, Caceres A, Kosik KS (1993) Intraneuronal compartments of the amyloid precursor protein. J Neurosci 13:3112–3123Google Scholar
  9. 9.
    Forman MS, Trojanowski JQ, Lee VM-Y (2004) Neurodegenerative diseases: a decade of revolutionary discoveries paves the way for therapeutic breakthroughs. Nat Med 10:1055–1063Google Scholar
  10. 10.
    Gajdusek DC (1985) Hypothesis: Interference with axonal transport of neurofilament as a common pathogenetic mechanism in certain diseases of the central nervous system. N Engl J Med 312:714–719Google Scholar
  11. 11.
    Gunawardena S, Goldstein LS (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32:389–401CrossRefPubMedGoogle Scholar
  12. 12.
    Gunawardena S, Goldstein LS (2004) Cargo-carrying motor vehicles on the neuronal highway: transport pathways and neurodegenerative disease. J Neurobiol 58:258–271CrossRefPubMedGoogle Scholar
  13. 13.
    Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX, et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775PubMedGoogle Scholar
  14. 14.
    Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, Lalli G, Witherden AS, Hummerich H, Nicholson S, et al (2003) Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300:808–812CrossRefPubMedGoogle Scholar
  15. 15.
    Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, Davoine CS, Cruaud C, Durr A, Wincker P, et al (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 23:296–303CrossRefPubMedGoogle Scholar
  16. 16.
    Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A, et al (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282:1914–1917CrossRefPubMedGoogle Scholar
  17. 17.
    Higuchi M, Lee VM-Y, Trojanowski JQ (2002) Tau and axonopathy in neurodegenerative disorders. Neuromolecular Med 2:131–150CrossRefPubMedGoogle Scholar
  18. 18.
    Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK, Trojanowski JQ, Lee VM-Y (1999) Age-dependent emergence and progression of a tauopathy in transgenic mice engineered to overexpress the shortest human tau isoform. Neuron 24:751–762CrossRefPubMedGoogle Scholar
  19. 19.
    Jensen PH, Nielsen MS, Jakes R, Dotti CG, Goedert M (1998) Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson’s disease mutation. 273:26292–26294Google Scholar
  20. 20.
    Jensen PH, Li JY, Dahlstrom A, Dotti CG (1999) Axonal transport of synucleins is mediated by all rate components. Eur J Neurosci 11:3369–3376Google Scholar
  21. 21.
    Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS (1993) Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. J Neurosci 13:3112–3123Google Scholar
  22. 22.
    King SJ, Schroer TA (2000) Dynactin increases the processivity of the cytoplasmic dynein motor. Nat Cell Biol 2:20–24Google Scholar
  23. 23.
    Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport Proc Natl Acad Sci USA 87:1561–1565Google Scholar
  24. 24.
    Kotzbauer P, Giasson B, Kravitz A, Golbe LI, Mark MH, Trojanowski JQ, Lee, VM-Y (2004) In vitro and postmortem brain studies link fibrillization of both alpha-synuclein and tau to familial Parkinson’s disease caused by the A53T alpha-synuyclein mutation. Exp Neurol 187:279–288CrossRefPubMedGoogle Scholar
  25. 25.
    LaMonte BH, Wallace KE, Holloway BA, Shelly SS, Ascano J, Tokito M, Van Winkle T, Howland DS, Holzbaur EL (2002) Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34:715–727CrossRefPubMedGoogle Scholar
  26. 26.
    Lasek RJ, Garner JA, Brady ST (1984) Axonal transport of the cytoplasmic matrix. J Cell Biol 99:212–221CrossRefGoogle Scholar
  27. 27.
    Lee VM-Y, Daughenbaugh R, Trojanowski JQ (1994) Microtubule stabilizing drugs for the treatment of Alzheimer’s disease. Neurobiol Aging 15:S87–S89CrossRefPubMedGoogle Scholar
  28. 28.
    Li W, Hoffman PN, Stirling W, Price DL, Lee MK (2004) Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson’s disease-linked mutations. J Neurochem 88:401–410PubMedGoogle Scholar
  29. 29.
    McDermott CJ, White K, Bushby K, Shaw PJ (2000) Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry 69:150–160CrossRefPubMedGoogle Scholar
  30. 30.
    Morfini G, Szebenyi G, Elluru R, Ratner N, Brady ST (2002) Glycogen synthase kinase-3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 21:281–293CrossRefPubMedGoogle Scholar
  31. 31.
    Muresan V (2000) One axon, many kinesins: What’s the logic? J Neurocytol 29:799–818CrossRefPubMedGoogle Scholar
  32. 32.
    Murphy DD, Rueter SM, Trojanowski JQ, Lee VM (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20:3214–3220PubMedGoogle Scholar
  33. 33.
    Nakagawa T, Tanaka Y, Matsuoka E, Kondo S, Okada Y, Noda Y, Kanai Y, Hirokawa N (1997) Identification and classification of 16 new kinesin superfamily (KIF) proteins in mouse genome. Proc Natl Acad Sci USA 94:9654–9659Google Scholar
  34. 34.
    Norris EH, Giasson BI, Lee VM (2004) Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 60:17–54PubMedGoogle Scholar
  35. 35.
    Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J (2003)Alzheimer’s presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci 23:4499–4508Google Scholar
  36. 36.
    Prudhomme JF, Brice A, Fontaine B, Heilig B, Weissenbach J (1999) Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat Genet 23:296–303CrossRefPubMedGoogle Scholar
  37. 37.
    Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, et al (2003) Mutant dynactin in motor neuron disease. Nat Genet 33:455–456Google Scholar
  38. 38.
    Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA, et al (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 71:1189–1194CrossRefPubMedGoogle Scholar
  39. 39.
    Roy S, Coffee P, Smith G, Liem RKH, Brady ST, Black MM (2000) Neurofilaments are transported rapidly but intermittently in axons: implications for slow axonal transport. J Neurosci 20:6849–6861Google Scholar
  40. 40.
    Szebenyi G, Morfini GA, Babcock A, Gould M, Selkoe K, Stenoien DL, Young M, Faber PW, MacDonald ME, McPhaul MJ, Brady ST (2003) Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40:41–52CrossRefPubMedGoogle Scholar
  41. 41.
    Takashima A, Murayama M, Murayama O, Kohno T, Honda T, Yasutake K, Nihonmatsu N, Mercken M, Yamaguchi H, Sugihara S, Wolozin B (1998) Presenilin 1 associates with glycogen synthase kinase-3 beta and its substrate tau. Proc Natl Acad Sci USA 95:9637–9641Google Scholar
  42. 42.
    Tesseur I, Van Dorpe J, Bruynseels K, Bronfman F, Sciot R, Van Lommel A, Van Leuven F (2000) Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol 157:1495–1510PubMedGoogle Scholar
  43. 43.
    Trojanowski JQ, Mattson MP (2003) Overview of protein aggregation in single, double, and triple neurodegenerative brain amyloidoses. Neuromolecular Med 4:1–6Google Scholar
  44. 44.
    Trojanowski JQ, Ishihara T, Higuchi M, Yoshiyama Y, Hong M, Zhang B, Forman MS, Zhukareva V, Lee VM-Y (2002) Amyotrophic lateral sclerosis/parkinsonism dementia complex: transgenic mice provide insights into mechanisms underlying a common tauopathy in an ethnic minority on Guam. Exp Neurol 176:1–11Google Scholar
  45. 45.
    Vale RD (2003) The molecular motor toolbox for intracellular transport. Cell 112:467–480CrossRefPubMedGoogle Scholar
  46. 46.
    Verhey KJ, Meyer D, Deehan R, Blenis J, Schnapp BJ, Rapoport TA, Margolis B (2001) Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J Cell Biol 152:959–970CrossRefPubMedGoogle Scholar
  47. 47.
    Wang L, Ho C-L, Sun D, Liem RKH, Brown A (2000) Rapid movement of axonal neurofilaments interrupted by prolonged pauses. Nat Cell Biol 2:137–141Google Scholar
  48. 48.
    Waterman-Storer CM, Karki S, Kuznetsov SA, Tabb JS, Weiss DG, Langford GM, Holzbaur ELF (1997) The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport. Proc Natl Acad Sci USA 94:12180–12185Google Scholar
  49. 49.
    Williamson TL, Cleveland DW (1999) Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nat Neurosci 2:50–56Google Scholar
  50. 50.
    Zhang B, Tu P-H, Abtahian F, Trojanowski JQ, Lee VM-Y (1997) Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation. J Cell Biol 139:1307–1315CrossRefPubMedGoogle Scholar
  51. 51.
    Zhang B, Higuchi M, Yoshiyama Y, Forman MS, Ishihara T, Hong M, Trojanowski JQ, Lee VM-Y (2004) Retarded axonal transport of R406W mutant tau in transgenic mice with a neurodegenerative tauopathy. J Neurosci 24:4657–4667Google Scholar
  52. 52.
    Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J, Lee EB, Xie SX, Joyce S, Li C, Toleikis PM, et al (2004) Microtubule binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a murine neurodegenerative tauopathy model. Proc Natl Acad Sci (in press)Google Scholar
  53. 53.
    Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, et al (2001) Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105:587–597CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Subhojit Roy
    • 1
  • Bin Zhang
    • 1
  • Virginia M.-Y. Lee
    • 1
  • John Q. Trojanowski
    • 1
  1. 1.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, and Institute on AgingUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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