Tau Released from Paired Helical Filaments with Formic Acid or Guanidine Is Susceptible to Calpain‐Mediated Proteolysis

Ling, Yang; Gordon‐Krajcer, Wanda; Księżak-Reding, Hanna

doi:10.1046/j.1471-4159.1997.69041548.x

Cited by 24 publications

(14 citation statements)

References 38 publications

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“…The amount of microtubules formed in the presence of phosphorylated P301L, V337M, and R406W is 1.7-, 1.5-, and 2. Previous studies have shown that ϳ60-, 64-, and 68-kDa tau bands of AD brain are also immunoreactive to PHF-1 antibody specific for Ser 396/404 -phosphorylated tau (51). This observation suggests that Ser 396/404 phosphorylation may also promote the formation of ϳ60-, 64-, and 68-kDa tau bands in the brain.…”

Section: Discussionmentioning

confidence: 69%

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro

Han

Qureshi

et al. 2009

Journal of Biological Chemistry

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In Alzheimer disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and other tauopathies, tau accumulates and forms paired helical filaments (PHFs) in the brain. Tau isolated from PHFs is phosphorylated at a number of sites, migrates as ϳ60-, 64-, and 68-kDa bands on SDS-gel, and does not promote microtubule assembly. Upon dephosphorylation, the PHF-tau migrates as ϳ50 -60-kDa bands on SDS-gels in a manner similar to tau that is isolated from normal brain and promotes microtubule assembly. The site(s) that inhibits microtubule assembly-promoting activity when phosphorylated in the diseased brain is not known. In this study, when tau was phosphorylated by Cdk5 in vitro, its mobility shifted from ϳ60-kDa bands to ϳ64-and 68-kDa bands in a time-dependent manner. This mobility shift correlated with phosphorylation at Ser 202 , and Ser 202 phosphorylation inhibited tau microtubule-assembly promoting activity. When several tau point mutants were analyzed, G272V, P301L, V337M, and R406W mutations associated with FTDP-17, but not nonspecific mutations S214A and S262A, promoted Ser 202 phosphorylation and mobility shift to a ϳ68-kDa band. Furthermore, Ser 202 phosphorylation inhibited the microtubule assembly-promoting activity of FTDP-17 mutants more than of WT. Our data indicate that FTDP-17 missense mutations, by promoting phosphorylation at Ser 202 , inhibit the microtubule assembly-promoting activity of tau in vitro, suggesting that Ser 202 phosphorylation plays a major role in the development of NFT pathology in AD and related tauopathies. Neurofibrillary tangles (NFTs)4 and senile plaques are the two characteristic neuropathological lesions found in the brains of patients suffering from Alzheimer disease (AD).The major fibrous component of NFTs are paired helical filaments (PHFs) (for reviews see Refs. 1-3). Initially, PHFs were found to be composed of a protein component referred to as "A68" (4). Biochemical analysis reveled that A68 is identical to the microtubule-associated protein, tau (4, 5). Some characteristic features of tau isolated from PHFs (PHF-tau) are that it is abnormally hyperphosphorylated (phosphorylated on more sites than the normal brain tau), does not bind to microtubules, and does not promote microtubule assembly in vitro. Upon dephosphorylation, PHF-tau regains its ability to bind to and promote microtubule assembly (6, 7). Tau hyperphosphorylation is suggested to cause microtubule instability and PHF formation, leading to NFT pathology in the brain (1-3).PHF-tau is phosphorylated on at least 21 proline-directed and non-proline-directed sites (8, 9). The individual contribution of these sites in converting tau to PHFs is not entirely clear. However, some sites are only partially phosphorylated in PHFs (8), whereas phosphorylation on specific sites inhibits the microtubule assembly-promoting activity of tau (6, 10). These observations suggest that phosphorylation on a few sites may be responsible and sufficient for causing tau dysfunction in AD.Tau purified ...

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Section: Discussionmentioning

confidence: 69%

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro

Han

Qureshi

et al. 2009

Journal of Biological Chemistry

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“…Results of previous studies have suggested that because of its fibrillary conformation aggregated tau is less susceptible to protease cleavage (36,37). However, no information is available regarding the generation of specific cleavage products when aggregated tau is exposed to calpain.…”

Section: The Aggregation Of Full-length Tau Into Filaments As Well Asmentioning

confidence: 99%

Calpain-Mediated Tau Cleavage: A Mechanism Leading to Neurodegeneration Shared by Multiple Tauopathies

Ferreira

Bigio

2011

Mol Med

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Tau dysfunction has been associated with a host of neurodegenerative diseases called tauopathies. These diseases share, as a common pathological hallmark, the presence of intracellular aggregates of hyperphosphorylated tau in affected brain areas. Aside from tau hyperphosphorylation, little is known about the role of other posttranslational modifications in tauopathies. Recently, we obtained data suggesting that calpain-mediated tau cleavage leading to the generation of a neurotoxic tau fragment might play an important role in Alzheimer's disease. In the current study, we assessed the presence of this tau fragment in several tauopathies. Our results show high levels of the 17-kDa tau fragment and enhanced calpain activity in the temporal cortex of AD patients and in brain samples obtained from patients with other tauopathies. In addition, our data suggest that this fragment could partially inhibit tau aggregation. Conversely, tau aggregation might prevent calpain-mediated cleavage, establishing a feedback circuit that might lead to the accumulation of this toxic tau fragment. Collectively, these data suggest that the mechanism underlying the generation of the 17-kDa neurotoxic tau fragment might be part of a conserved pathologic process shared by multiple tauopathies.

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“…Several studies showed that tau can be degraded by calpains and phosphorylation can retard this process [35][36][37]. On the basis of the P2-P1 rule, nine potential calpain cleavage sites have been suggested for tau [38].…”

Section: Calpainsmentioning

confidence: 99%

Proteolytic processing of tau

Wang

Garg

Mandelkow

2010

Biochemical Society Transactions

110

100

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Tau aggregation is a hallmark of several neurodegenerative diseases, including AD (Alzheimer's disease), although the mechanism underlying tau aggregation remains unclear. Recent studies show that the proteolysis of tau plays an important role in both tau aggregation and neurodegeneration. On one hand, truncation of tau may generate amyloidogenic tau fragments that initiate the aggregation of tau, which in turn can cause toxicity. On the other hand, truncation of tau may result in tau fragments which induce neurodegeneration through unknown mechanisms, independently of tau aggregation. Blocking the truncation of tau thus may represent a promising therapeutic approach for AD or other tauopathies. In the present paper, we summarize our data on tau cleavage in a cell model of tauopathy and major results on tau cleavage reported in the literature.

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Tau Released from Paired Helical Filaments with Formic Acid or Guanidine Is Susceptible to Calpain‐Mediated Proteolysis

Cited by 24 publications

References 38 publications

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro

Calpain-Mediated Tau Cleavage: A Mechanism Leading to Neurodegeneration Shared by Multiple Tauopathies

Proteolytic processing of tau

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