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Cited by 379Hereditary Neurological DisordersAmyotrophic Lateral Sclerosis ResearchMicrotubule and mitosis dynamics

Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila

Hurd, Daryl D, Saxton, William M·1996·Genetics
DOI 10.1093/genetics/144.3.1075
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Abstract

Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in those diseases.

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  • Overexpression of WT and FAD mutant human APP and Drosophila APPL in the Drosophila larval nervous system causes axonal blockages reminiscent of those found in mutants for molecular motors.

    “Previous work showed that overexpression of WT and FAD mutant human APP and Drosophila APPL in the Drosophila larval nervous system causes axonal blockages reminiscent of those found in mutants for molecular motors (29,30,50).”

    From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [50]

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Research works printed but not linked: 5

  1. DLJBRE~JII., R. R., and J. Y I ~, 1994 Ankyrin and P-spectrin accumulate independently of a-spectrin in Drosophila. Proc. Natl. Acad. Sci.
  2. IAMBF.RI, E. H., and P. J. DYCK, 1993 Compound action potentials of sural nerve in vitro in peripheral neuropathy, pp. 672-685 in I'priphrral Ahropathy, edited by P. J. DYCK, P. K. THOMAS, J. W. GRIFFIN. P. A. L , o w and,J. F. PoDr:sI.o. W. B. Saunders, Philadel- phia.
  3. HIROKAWA, N., R. %TO-YOSHITAKE, N. KOBAYASHI, K. K. PFISTER, G. s. LINDSIXY, D. L., and G. G. ZIMM, 1992 The Genolnc of Drosophila melanogarter. Academic Press, San Diego.
  4. OCHS, s., and W. s. BRIMIIOIN, 1993 Axonal transport, pp. 331-360 in Peri>herd Neuropathy, edited by P. J. DYCK, P. K. THOMAS, J. W. GKIFFIN, P. A. LOW and J. F. PODUSIX). W. B. Saunders, Philadel- phia.
  5. ROWAND, L. P., 1994 Natural history and clinical features of amyo- trophic lateral sclerosis, pp. 507-522 in A;rurorlegpnrrativeDisf~asps, edited by D. B. CNX.E. W. B. Saunders Co., Philadelphia.

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Authors
Hurd, D. D., & Saxton, W. M.
Affiliations
Indiana University Bloomington (US)
Corresponding author
Saxton, William M
Venue
Genetics
Publisher
Oxford University Press (OUP)
Published
1996-11-01
Volume
144
Issue
3
Pages
1075-1085
ISSN
  • 0016-6731 (ISSN-L)
  • 1943-2631
DOI
10.1093/genetics/144.3.1075
OpenAlex
W1877780738
Cited by
379
References
41
Citations by year
2026: 1 · 2025: 8 · 2024: 9 · 2023: 14 · 2022: 8 · 2021: 10 · 2020: 8 · 2019: 7 · 2018: 11 · 2017: 16 · 2016: 11 · 2015: 14 · 2014: 18 · 2013: 18 · 2012: 22
FWCI
3.52
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health (5t32gm007227-21)
  • National Institute of General Medical Sciences (T32GM-07227, R01GM046295, GM-46295)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords
kinesin heavy chain, motor neuron disease, fast axonal transport, retrograde transport, anterograde transport, axonal swellings, organelle transport, synaptic boutons, neurotransmitter release, amyotrophic lateral sclerosis, Drosophila
MeSH terms
Animals, Axons, Biological Transport, Calcium-Binding Proteins, Drosophila, Female, Male, Membrane Glycoproteins, Membrane Proteins, Nerve Tissue Proteins, Paralysis, Phenotype, Rabbits, Organelles, Cell Adhesion Molecules, Neuronal, Mutagenesis, Motor Neuron Disease, Kinesins, Presynaptic Terminals, Animals, Genetically Modified, Qa-SNARE Proteins, Synaptotagmins, HSP40 Heat-Shock Proteins, Mice

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