Endogenous GSK-3/Shaggy regulates bidirectional axonal transport of the amyloid precursor protein

Carole Weaver, Christina Leidel, Lukasz Szpankowski, Nicole M. Farley, George Shubeita, Lawrence S.B. Goldstein

    Research output: Contribution to journalArticle

    Abstract

    Neurons rely on microtubule (MT) motor proteins such as kinesin-1 and dynein to transport essential cargos between the cell body and axon terminus. Defective axonal transport causes abnormal axonal cargo accumulations and is connected to neurodegenerative diseases, including Alzheimer's disease (AD). Glycogen synthase kinase 3 (GSK-3) has been proposed to be a central player in AD and to regulate axonal transport by the MT motor protein kinesin-1. Using genetic, biochemical and biophysical approaches in Drosophila melanogaster, we find that endogenous GSK-3 is a required negative regulator of both kinesin-1-mediated and dynein-mediated axonal transport of the amyloid precursor protein (APP), a key contributor to AD pathology. GSK-3 also regulates transport of an unrelated cargo, embryonic lipid droplets. By measuring the forces motors generate in vivo, we find that GSK-3 regulates transport by altering the activity of kinesin-1 motors but not their binding to the cargo. These findings reveal a new relationship between GSK-3 and APP, and demonstrate that endogenous GSK-3 is an essential in vivo regulator of bidirectional APP transport in axons and lipid droplets in embryos. Furthermore, they point to a new regulatory mechanism in which GSK-3 controls the number of active motors that are moving a cargo.

    Original languageEnglish (US)
    Pages (from-to)295-308
    Number of pages14
    JournalTraffic
    Volume14
    Issue number3
    DOIs
    StatePublished - Mar 1 2013

    Fingerprint

    Glycogen Synthase Kinase 3
    Axonal Transport
    Amyloid beta-Protein Precursor
    Kinesin
    Microtubule Proteins
    Dyneins
    Alzheimer Disease
    Axons
    Neurodegenerative diseases
    Lipids
    Pathology
    Protein Transport
    Drosophila melanogaster
    Amyloid
    Neurodegenerative Diseases
    Neurons
    Molecular Biology
    Proteins
    Embryonic Structures
    Cells

    Keywords

    • Alzheimer's
    • Amyloid precursor protein
    • Axonal transport
    • Dynein
    • GSK-3
    • Kinesin
    • Lipid droplets
    • Optical trap

    ASJC Scopus subject areas

    • Structural Biology
    • Biochemistry
    • Molecular Biology
    • Genetics
    • Cell Biology

    Cite this

    Weaver, C., Leidel, C., Szpankowski, L., Farley, N. M., Shubeita, G., & Goldstein, L. S. B. (2013). Endogenous GSK-3/Shaggy regulates bidirectional axonal transport of the amyloid precursor protein. Traffic, 14(3), 295-308. https://doi.org/10.1111/tra.12037

    Endogenous GSK-3/Shaggy regulates bidirectional axonal transport of the amyloid precursor protein. / Weaver, Carole; Leidel, Christina; Szpankowski, Lukasz; Farley, Nicole M.; Shubeita, George; Goldstein, Lawrence S.B.

    In: Traffic, Vol. 14, No. 3, 01.03.2013, p. 295-308.

    Research output: Contribution to journalArticle

    Weaver, C, Leidel, C, Szpankowski, L, Farley, NM, Shubeita, G & Goldstein, LSB 2013, 'Endogenous GSK-3/Shaggy regulates bidirectional axonal transport of the amyloid precursor protein', Traffic, vol. 14, no. 3, pp. 295-308. https://doi.org/10.1111/tra.12037
    Weaver C, Leidel C, Szpankowski L, Farley NM, Shubeita G, Goldstein LSB. Endogenous GSK-3/Shaggy regulates bidirectional axonal transport of the amyloid precursor protein. Traffic. 2013 Mar 1;14(3):295-308. https://doi.org/10.1111/tra.12037
    Weaver, Carole ; Leidel, Christina ; Szpankowski, Lukasz ; Farley, Nicole M. ; Shubeita, George ; Goldstein, Lawrence S.B. / Endogenous GSK-3/Shaggy regulates bidirectional axonal transport of the amyloid precursor protein. In: Traffic. 2013 ; Vol. 14, No. 3. pp. 295-308.
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