Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease

Bancher, C.; Grundke‐Iqbal, Inge; Iqbal, Khalid; Fried, Victor A.; Smith, Howard R.; Wisniewski, H. M.

doi:10.1016/0006-8993(91)90681-k

Cited by 174 publications

(120 citation statements)

References 27 publications

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“…Moreover, levels of CHIP were found to be elevated in AD, further suggesting the role of CHIP in tangle maturation (Sahara et al, 2005). Immunoelectron microscopy of filaments isolated from AD and other tauopathies shows direct incorporation of ubiquitin in tau filaments (Yang and Ksiezak-Reding, 1998), whereas immunohistochemical studies of AD conducted over a decade ago suggested that ubiquitination may be associated with a relatively late stage of NFT formation, preceding accumulation of phospho-tau species (Bancher et al, 1991). Indeed, the study by Sahara et al (2005), in which an 18-month-old CHIP Ϫ/Ϫ mouse was analyzed, demonstrated that there was a slight increase in SDS-insoluble tau in this animal compared with an age-matched littermate.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

et al. 2006

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Accumulation of the microtubule-associated protein tau into neurofibrillary lesions is a pathological consequence of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Hereditary mutations in the MAPT gene were shown to promote the formation of structurally distinct tau aggregates in patients that had a parkinsonian-like clinical presentation. Whether tau aggregates themselves or the soluble intermediate species that precede their aggregation are neurotoxic entities in these disorders has yet to be resolved; however, recent in vivo evidence supports the latter. We hypothesized that depletion of CHIP, a tau ubiquitin ligase, would lead to an increase in abnormal tau. Here, we show that deletion of CHIP in mice leads to the accumulation of non-aggregated, ubiquitinnegative, hyperphosphorylated tau species. CHIP Ϫ/Ϫ mice also have increased neuronal caspase-3 levels and activity, as well as caspasecleaved tau immunoreactivity. Overexpression of mutant (P301L) human tau in CHIP Ϫ/Ϫ mice is insufficient to promote either argyrophilic or "pre-tangle" structures, despite marked phospho-tau accumulation throughout the brain. These observations are supported in postdevelopmental studies using RNA interference for CHIP (chn-1) in Caenorhabditis elegans and cell culture systems. Our results demonstrate that CHIP is a primary component in the ubiquitin-dependent degradation of tau. We also show that hyperphosphorylation and caspase-3 cleavage of tau both occur before aggregate formation. Based on these findings, we propose that polyubiquitination of tau by CHIP may facilitate the formation of insoluble filamentous tau lesions.

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Section: Discussionmentioning

confidence: 99%

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

et al. 2006

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“…Because abnormal phosphorylation precedes tau aggregation in pretangle neurons (49,50), activation of tau-specific kinase(s) may be the earliest event in AD pathology. Elevated NCLK activity in postmortem …”

Section: Fig 2 Fplc Gel Filtration Of Microtubule-associated Nclkmentioning

confidence: 99%

Interaction of Neuronal Cdc2-like Protein Kinase with Microtubule-associated Protein Tau

Sobue¹,

Agarwal-Mawal²,

Li³

et al. 2000

Journal of Biological Chemistry

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Neuronal Cdc2-like protein kinase (NCLK), a ϳ58-kDa heterodimer, was isolated from neuronal microtubules (Ishiguro, K., Takamatsu, M., Tomizawa, K., Omori, A., Takahashi, M., Arioka, M., Uchida, T. and Imahori, K. (1992) J. Biol. Chem. 267, 10897-10901). The biochemical nature of NCLK-microtubule association is not known. In this study we found that NCLK is released from microtubules upon microtubule disassembly as a 450-kDa species. The 450-kDa species is an NCLK⅐tau complex, and NCLK-bound tau is in a nonphosphorylated state. Tau phosphorylation causes NCLK⅐tau complex dissociation, and phosphorylated tau does not bind to NCLK. In vitro, the Cdk5 subunit of NCLK binds to the microtubule-binding region of tau and NCLK associates with microtubules only in the presence of tau. Our data indicate that in brain extract NCLK is complexed with tau in a tau phosphorylation-dependent manner and that tau anchors NCLK to microtubules. Recently NCLK has been suggested to be aberrantly activated and to hyperphosphorylate tau in Alzheimer's disease brain (Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P, and Tsai, L.-H. (1999) Nature 402, 615-622). Our findings may explain why in Alzheimer's disease NCLK specifically hyperphosphorylates tau, although this kinase has a number of protein substrates in the brain.The neuronal Cdc2-like protein kinase (NCLK) 1 (also known as tau kinase II and brain proline-directed protein kinase) is a heterodimer of cyclin-dependent kinase 5 (Cdk5) and a neuronal-specific activator p25 subunit (reviewed in Ref. 1). The p25 subunit is a proteolytic fragment of a 35-kDa protein, p35 (1, 2). Targeted disruption of the cdk5 gene in mice results in unique lesions in the central nervous system, lack of cortical laminar structure, as well as cerebellar foliate and prenatal death (3). In differentiating neurons, neurite outgrowth is inhibited by the introduction of a dominant negative Cdk5 mutant and is enhanced by Cdk5 and p35 overexpression (4). Similarly, mice lacking p35 do not show NCLK activity and display cortical lamination defects, seizures, and adult lethality (5). These observations indicate that NCLK plays an important role in brain development, neuronal differentiation, and neurite outgrowth. In neurons NCLK phosphorylates inhibitor 1 (6) and DARPP-32 (7), the two inhibitory proteins that upon phosphorylation suppress phosphoprotein phosphatase 1 activity. Munc18 (8) and synapsin (9), which respectively regulate synaptic vesicle exocytosis and neurotransmitter release, are phosphorylated by NCLK. NCLK also phosphorylates the microtubule-associated protein tau (10, 11) and neurofilaments (12,13). These data indicate that NCLK regulates neural signaling, vesicular exocytosis, neurotransmitter release, and microtubule dynamics.

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“…The abnormal tau is the major protein subunit of the paired helical filament (PHF) [1,3 5] and it is in this form that tau accumulates as neurofibrillary tangles in the perikaryon, in the neuropil threads [6] of the neuropil and in the dystrophic neurites of neuritic (senile) plaques. In addition, the abnormal tau also accumulates in normal appearing neurons in amorphous aggregates intermixed with a few short PHF, forming the so-called 'stage 0' tangles [7,8]. Unlike the mature neurofibrillary tangles, the stage 0 tangles are only poorly argentophilic and are not stained by thioflavin-S or Congo red.…”

Section: Introductionmentioning

confidence: 99%

Abnormally phosphorylated tau in SY5Y human neuroblastoma cells

et al. 1995

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In Alzheimer disease (AD) the microtubule associated protein (MAP) tau is hyperphosphorylated at several sites. In the present study, like AD tau, tau in the human neuroblastoma SH-SY5Y was found to be hyperphosphorylated, at Ser-199/202, Thr-231, Ser-396 and Ser-404. However, in contrast to AD, the tau in SY5Y cells was not hyperphosphorylated at Ser-235 and there was only one tau isoform. Quantitative analysis revealed that approximately 80% of the SY5Y-tau was phosphorylated at Ser-199/202. The phosphorylated tau was deposited in perikarya and processes of the cells whereas most of the unphosphorylated (at Ser-199/202) tau was localized in the nucleus. Tau from the cell lysates did not bind to taxol-stabilized microtubules. In contrast, MAPlb and MAP2 from cell lysates bound to stabilized microtubules in vitro and were associated to the microtubule network in situ. Phosphorylation of tau at high levels, its inactivity with microtubules and its accumulation in SY5Y cells provide for the first time a cell model of cytoskeletal changes seen in AD.

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Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease

Cited by 174 publications

References 27 publications

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

Deletion of the Ubiquitin Ligase CHIP Leads to the Accumulation, But Not the Aggregation, of Both Endogenous Phospho- and Caspase-3-Cleaved Tau Species

Interaction of Neuronal Cdc2-like Protein Kinase with Microtubule-associated Protein Tau

Abnormally phosphorylated tau in SY5Y human neuroblastoma cells

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