14-3-3ζ Mediates Tau Aggregation in Human Neuroblastoma M17 Cells

• Published in: PloS one Vol. 11; no. 8; p. e0160635
• Main Authors: Li, Tong, Paudel, Hemant K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2016; Public Library of Science (PLoS)
• Subjects: 14-3-3 Proteins - genetics; 14-3-3 Proteins - metabolism; Agglomeration; Aging; Alzheimer's disease; Alzheimers disease; Biochemistry; Biology and Life Sciences; Brain; Brain research; Cell division; Cell Line, Tumor; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Filaments; Gene Expression; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Humans; Immunoglobulins; Kinases; Medical research; Medicine and Health Sciences; Microtubule-associated proteins; Microtubules - metabolism; Microtubules - ultrastructure; Neuroblastoma; Neuroblastoma cells; Neurons - metabolism; Neurons - ultrastructure; Phosphatase; Phosphorylation; Physical Sciences; Protein Aggregates; Protein Binding; Protein kinase A; Proteins; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Research and Analysis Methods; Signal transduction; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Canada; Montreal Quebec Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0160635

Microtubule-associated protein tau is the major component of paired helical filaments (PHFs) associated with the neuropathology of Alzheimer's disease (AD). Tau in the normal brain binds and stabilizes microtubules. Tau isolated from PHFs is hyperphosphorylated, which prevents it from binding to microtubules. Tau phosphorylation has been suggested to be involved in the development of NFT pathology in the AD brain. Recently, we showed that 14-3-3ζ is bound to tau in the PHFs and when incubated in vitro with 14-3-3ζ, tau formed amorphous aggregates, single-stranded straight filaments, double stranded ribbon-like filaments and PHF-like filaments that displayed close resemblance with corresponding ultrastructures of AD brain. Surprisingly however, phosphorylated and non-phosphorylated tau aggregated in a similar manner, indicating that tau phosphorylation does not affect in vitro tau aggregation (Qureshi et al (2013) Biochemistry 52, 6445-6455). In this study, we have examined the role of tau phosphorylation in tau aggregation in cellular level. We have found that in human M17 neuroblastoma cells, tau phosphorylation by GSK3β or PKA does not cause tau aggregation, but promotes 14-3-3ζ-induced tau aggregation by destabilizing microtubules. Microtubule disrupting drugs also promoted 14-3-3ζ-induced tau aggregation without changing tau phosphorylation in M17 cell. In vitro, when incubated with 14-3-3ζ and microtubules, nonphosphorylated tau bound to microtubules and did not aggregate. Phosphorylated tau on the other hand did not bind to microtubules and aggregated. Our data indicate that microtubule-bound tau is resistant to 14-3-3ζ-induced tau aggregation and suggest that tau phosphorylation promotes tau aggregation in the brain by detaching tau from microtubules and thus making it accessible to 14-3-3ζ.