Interaction of tau protein with the dynactin complex.
Tau is an axonal microtubule-associated protein involved in microtubule assembly and stabilization. Mutations in Tau cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and tau aggregates are present in Alzheimer's disease and other tauopathies. The mechanisms leading from tau dysfunction to neurodegeneration are still debated. The dynein-activator complex dynactin has an essential role in axonal transport and mutations in its gene are associated with lower motor neuron disease. We show here for the first time that the N-terminal projection domain of tau binds to the C-terminus of the p150 subunit of the dynactin complex. Tau and dynactin show extensive colocalization, and the attachment of the dynactin complex to microtubules is enhanced by tau. Mutations of a conserved arginine residue in the N-terminus of tau, found in patients with FTDP-17, affect its binding to dynactin, which is abnormally distributed in the retinal ganglion cell axons of transgenic mice expressing human tau with a mutation in the microtubule-binding domain. These findings, which suggest a direct involvement of tau in axonal transport, have implications for understanding the pathogenesis of tauopathies.
Magnani
Enrico
E
Department of Clinical Neurosciences, Brain Repair Centre, University of Cambridge, Cambridge, UK.
Fan
Juan
J
Gasparini
Laura
L
Golding
Matthew
M
Williams
Meredith
M
Schiavo
Giampietro
G
Goedert
Michel
M
Amos
Linda A
LA
Spillantini
Maria Grazia
MG
D000818:Animals; D001120:Arginine / Q000737:chemistry; D001369:Axons / Q000378:metabolism; D003001:Cloning, Molecular; D000072159:Dynactin Complex; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020798:Two-Hybrid System Techniques; D016875:tau Proteins / Q000737:chemistry / Q000502:physiology*
D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D001120:Arginine