P3-228 Chip and HSP70 regulate tau ubiquitination, degradation and aggregation

Petrucelli, Leonard; Taylor, Julie P.; Kehoe, Kathryn; Lewis, Jada; McGowan, Eileen; Snyder, Heather M.; Wolozin, Ben; Dawson, Ted M.; Dillmann, Wolfgang H.; Voellmy, Richard; Hutton, Michael

doi:10.1016/s0197-4580(04)81378-2

Cited by 16 publications

(24 citation statements)

References 37 publications

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“…However, it has been unclear how this cleavage and aggregation may occur in neurons. The degradation of tau is thought to take place through the ubiquitin-proteasome pathway (30,31), but other mechanisms contribute as well, such as N-terminal shortening by aminopeptidases (20) or lysosomal proteases (32,33). Several types of tau truncation have been reported in cells or brain tissue, for example, behind E391 by an unknown protease (17), behind D421 by caspase 3 (18,19), cleavage sites in the N-terminal half by calpain generating a 17-kDa fragment (23), or fragments generated by thrombin-like proteases (21,22).…”

Section: Discussionmentioning

confidence: 99%

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model

Wang

Biernat

Pickhardt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

173

178

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Tau is a highly soluble protein, yet it aggregates abnormally in Alzheimer's disease. Here, we address the question of proteolytic processing of tau and the nucleation of aggregates by tau fragments. We show in neuronal cell models that fragments of the repeat domain of tau containing mutations of FTDP17 (frontotemporal dementia with parkinsonism linked to chromosome 17), produced by endogenous proteases, can induce the aggregation of full-length tau. Fragments are generated by successive cleavages, first N-terminally between K257 and S258, then C-terminally around residues 353-364; conversely, when the N-terminal cleavage is inhibited, no fragmentation and aggregation takes place. The C-terminal truncation and the coaggregation of fragments with full-length tau depends on the propensity for ␤-structure. The aggregation is modulated by phosphorylation but does not depend on it. Aggregation but not fragmentation as such is toxic to cells; conversely, toxicity can be prevented by inhibiting either aggregation or proteolysis. The results reveal a novel pathway of abnormal tau aggregation in neuronal cells.Alzheimer's disease ͉ paired helical filaments ͉ Tau protein ͉ frontotemporal dementia T he neurofibrillary pathology, based on the aggregation of tau protein into paired helical filaments (PHFs), is a hallmark of Alzheimer's disease (AD) and other tauopathies (1), and the distribution of tau deposits correlates with the loss of neurons (2). The discovery that mutations in the tau gene cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP17) (3) and tau aggregation provided evidence that abnormalities in tau were sufficient to cause neurodegeneration. Despite the development of transgenic mice that recapitulate some of the hallmarks of AD (4, 5), the mechanism of tau aggregation remains enigmatic.Tau is a natively unfolded protein that shows little tendency to aggregate in physiological buffers (6). However, aggregation can be dramatically accelerated by polyanionic cofactors such as sulfated glycosaminoglycans, RNA, acidic peptides, or fatty acid micelles (7-10). The aggregation is thought to follow a nucleation-elongation pathway (11), whereby an oligomeric nucleus is first formed by self-association of protein subunits, followed by addition of subunits to filament ends. However, several issues remain open in this scheme: (i) Although tau fragments aggregate spontaneously (12), full-length tau is difficult to fibrillize even at high concentration unless aided by polyanions. (ii) Seeding of recombinant tau with Alzheimer PHFs is inefficient without fibrillization inducers. (iii) The nature of the nucleating species of tau fibrils is not known.A further unsolved question is whether tau aggregation is cytotoxic. Because the occurrence of PHFs correlates with the loss of cognitive functions in AD, it is widely assumed that PHFs are one of the causes of neurodegeneration. On the other hand, neurons bearing PHFs can survive for a long time, and memory deficits in transgenic mice can occur indep...

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Section: Discussionmentioning

confidence: 99%

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model

Wang

Biernat

Pickhardt

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

173

178

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“…Akt and tau ubiquitination levels in HeLa and HEK293 cells was performed as previously described (18,19). Briefly, cell supernatants were incubated with capture antibodies and Fc binding protein overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Akt and CHIP coregulate tau degradation through coordinated interactions

Dickey¹,

Koren²,

Zhang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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200

174

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A hallmark of the pathology of Alzheimer's disease is the accumulation of the microtubule-associated protein tau into fibrillar aggregates. Recent studies suggest that they accumulate because cytosolic chaperones fail to clear abnormally phosphorylated tau, preserving a pool of toxic tau intermediates within the neuron. We describe a mechanism for tau clearance involving a major cellular kinase, Akt. During stress, Akt is ubiquitinated and degraded by the tau ubiquitin ligase CHIP, and this largely depends on the Hsp90 complex. Akt also prevents CHIP-induced tau ubiquitination and its subsequent degradation, either by regulating the Hsp90/CHIP complex directly or by competing as a client protein with tau for binding. Akt levels tightly regulate the expression of CHIP, such that, as Akt levels are suppressed, CHIP levels also decrease, suggesting a potential stress response feedback mechanism between ligase and kinase activity. We also show that Akt and the microtubule affinity-regulating kinase 2 (PAR1/MARK2), a known tau kinase, interact directly. Akt enhances the activity of PAR1 to promote tau hyperphosphorylation at S262/S356, a tau species that is not recognized by the CHIP/Hsp90 complex. Moreover, Akt1 knockout mice have reduced levels of tau phosphorylated at PAR1/MARK2 consensus sites. Hence, Akt serves as a major regulator of tau biology by manipulating both tau kinases and protein quality control, providing a link to several common pathways that have demonstrated dysfunction in Alzheimer's disease.Alzheimer's disease ͉ cell signaling ͉ chaperone ͉ MARK2/PAR1

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“…19 RD3 IP blots were probed with rabbit polyclonal phospho-tau antibodies and Alz50 IP blots were probed with RD3 antibody using mouse IgG-specific secondary detection to avoid capture antibody heavy chain interference.…”

Section: Immunoprecipitation With Rd3 and Alz50 Antibodiesmentioning

confidence: 99%

Aging Analysis Reveals Slowed Tau Turnover and Enhanced Stress Response in a Mouse Model of Tauopathy

Dickey

Kraft

Jinwal

et al. 2009

The American Journal of Pathology

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We have extensively analyzed the biochemical and histochemical profiles of the tau protein from the rTg4510 transgenic mouse model in which the animals uniquely develop forebrain tau pathologies similar to those found in human tauopathies. Levels of several soluble phosphorylated tau species were highest at 1 month relative to later time points, suggesting that certain tau hyperphosphorylation events were insufficient to drive tangle formation in young mice. Despite a robust, pre-tangle-like accumulation of phospho-tau in 1-month-old mice, this material was cleared by 3 months, indicating that the young mouse brain either fails to facilitate tau insolubility or possesses an enhanced ability to clear tau relative to the adult. We also found that while heat shock protein expression increased with normal aging, this process was accelerated in rTg4510 mice. Moreover, by exploiting an exon 10 (؊) specific antibody, we demonstrated that endogenous mouse tau turnover was slowed in response to human tau over-expression, and that this endogenous tau adopted disease-related properties. These data suggest that a younger brain fails to develop lasting tau pathology despite elevated levels of phosphorylated tau , perhaps because of reduced expression of stress-related proteins. Moreover , we show that the active production of small amounts of abnormal tau protein facilitates dysfunction and accumulation of otherwise normal tau , a significant implication for the pathogenesis of patients with Alzheimer's disease. (Am J Pathol

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P3-228 Chip and HSP70 regulate tau ubiquitination, degradation and aggregation

Cited by 16 publications

References 37 publications

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model

Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model

Akt and CHIP coregulate tau degradation through coordinated interactions

Aging Analysis Reveals Slowed Tau Turnover and Enhanced Stress Response in a Mouse Model of Tauopathy

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