Abstract
Phosphorylated forms of microtubule-associated protein tau accumulate in neurofibrillary tangles in Alzheimer's disease. To investigate the effects of specific phosphorylated tau residues on its function, wild type or phosphomutant tau was expressed in cells. Elevated tau phosphorylation decreased its microtubule binding and bundling, and increased the number of motile tau particles, without affecting axonal transport kinetics. In contrast, reducing tau phosphorylation enhanced the amount of tau bound to microtubules and inhibited axonal transport of tau. To determine whether differential tau clearance is responsible for the increase in phosphomimic tau, we inhibited autophagy in neurons which resulted in a 3-fold accumulation of phosphomimic tau compared with wild type tau, and endogenous tau was unaffected. In autophagy-deficient mouse embryonic fibroblasts, but not in neurons, proteasomal degradation of phosphomutant tau was also reduced compared with wild type tau. Therefore, autophagic and proteasomal pathways are involved in tau degradation, with autophagy appearing to be the primary route for clearing phosphorylated tau in neurons. Defective autophagy might contribute to the accumulaton of tau in neurodegenerative diseases.
Highlights
The microtubule-associated protein tau is a cytoskeletal protein expressed primarily in the central nervous system where it stabilizes microtubules and regulates neurite outgrowth
We have investigated the effect of tau phosphorylation on its rate of axonal transport and degradation
The tau phosphomimics, E18tau, and E27tau (Goedert et al, 1989; Smith et al, 2000), harbor glutamate substitutions of serine and threonine residues that correspond to many of those targeted by glycogen synthase kinase-3 (GSK-3), a candidate kinase for tau phosphorylation (Hanger et al, 2007)
Summary
The microtubule-associated protein tau is a cytoskeletal protein expressed primarily in the central nervous system where it stabilizes microtubules and regulates neurite outgrowth. Interaction of tau with microtubules occurs primarily through the repeated microtubule-binding domains located in the C-terminal half of tau. The inclusion of either 3 or 4 binding repeats is regulated by alternative splicing of exon 10, which gives rise to either 3R or 4R tau isoforms (Goedert et al, 1989). Tau interacts with components of the plasma membrane through its amino terminal projection domain (Brandt et al, 1995; GauthierKemper et al, 2011; Pooler et al, 2012). Phosphorylation of tau decreases its capacity to bind to and stabilize microtubules (Bramblett et al, 1993; Busciglio et al, 1995), and recently we have
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