Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration.
Missorting of Tau from axons to the somatodendritic compartment of neurons is a hallmark of Alzheimer's disease, but the mechanisms underlying normal sorting and pathological failure are poorly understood. Here, we used several Tau constructs labelled with photoconvertible Dendra2 to analyse its mobility in polarized neurons. This revealed a novel mechanism of sorting-a retrograde barrier in the axon initial segment (AIS) operating as cellular rectifier. It allows anterograde flow of axonal Tau but prevents retrograde flow back into soma and dendrites. The barrier requires binding of Tau to microtubules but does not require F-actin and thus is distinct from the sorting of membrane-associated proteins at the AIS. The barrier breaks down when Tau is phosphorylated in its repeat domain and detached from microtubules, for example, by the kinase MARK/Par1. These observations link the pathological hallmarks of Tau missorting and hyperphosphorylation in neurodegenerative diseases.
Max-Planck-Unit for Structural Molecular Biology, c/o DESY, Hamburg, Germany.
Xiaoyu
X
Li
Yatender
Y
Kumar
Hans
H
Zempel
Eva-Maria
EM
Mandelkow
Jacek
J
Biernat
Eckhard
E
Mandelkow
D000199:Actins / Q000378:metabolism; D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008164:Luminescent Proteins / Q000032:analysis; D008565:Membrane Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism* / Q000648:ultrastructure; D010766:Phosphorylation; D010777:Photochemistry / Q000379:methods; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism*
D000199:Actins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D016875:tau Proteins; D017346:Protein Serine-Threonine Kinases