Posttranslational modification and microtubule stability.

Schulze, Eric; Asai, David J.; Bulinski, J C; Kirschner, Marc W.

doi:10.1083/jcb.105.5.2167

Cited by 354 publications

(214 citation statements)

References 25 publications

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“…In addition to total tubulin and neuron-specific class III ␤-tubulin, we analyzed the levels of acetylated and detyrosinated tubulin as markers of stable microtubules and tyrosinated tubulin as a marker of unstable microtubules (29,30). No significant changes were detected in the content of total tubulin, acetylated tubulin, or class III neuron-specific tubulin in human tau transgenic or tau knockout mice when compared with wild-type untreated cultures (Table 2).…”

Section: Analysis Of the Complement Of Microtubular Proteins In Tau Kmentioning

confidence: 99%

Tau is essential to β-amyloid-induced neurotoxicity

Rapoport

Dawson

Binder

et al. 2002

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

739

527

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Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar ␤-amyloid peptide (A␤); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar A␤-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar A␤. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of A␤. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of A␤. These results provide direct evidence supporting a key role for tau in the mechanisms leading to A␤-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to A␤-mediated neurodegeneration.R ecent research on the field of Alzheimer's disease (AD) has been focused on the mechanisms leading to the formation of senile plaques and neurofibrillary tangles, the two hallmark lesions of this neurodegenerative disease. Both lesions are the result of the pathological deposition of proteins normally distributed throughout the brain. Senile plaques are extracellular deposits of fibrillar ␤-amyloid peptide (A␤), a cleavage product of the amyloid precursor protein (see refs. 1-5 and refs. therein). Neurofibrillary tangles, on the other hand, are intracellular bundles of self-assembled hyperphosphorylated tau proteins (6-10). Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. Indirect evidence from several studies using cultured neurons suggests a role for tau in the generation of dystrophic neurites in the presence of fibrillar A␤. The common picture emerging from these studies indicates that deposition of fibrillar A␤ induces phosphorylation of tau followed by progressive degeneration of neuronal processes (11-16). In addition, several groups have reported that kinases known to phosphorylate tau in vitro were activated in response to fibrillar A␤ deposition. When young neurons were incubated in the presence of fibrillar A␤, both GSK3␤ and CDK5 were activated (11, 17). In mature hippocampal neurons, on the other hand, fibrillar A␤-induced neurotoxicity was accompanied by the sustained activation of mitogen-activated protein kinase (MAPK) (14)(15)(16)18). Taken collectively, these results suggest a key role for tau in the generation of dystrophic neurites in response to fibrillar A␤ treatments. To obtain direct ev...

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Section: Analysis Of the Complement Of Microtubular Proteins In Tau Kmentioning

confidence: 99%

Tau is essential to β-amyloid-induced neurotoxicity

Rapoport

Dawson

Binder

et al. 2002

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

739

527

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“…S1). To test whether JNK TKO neurons exhibited increased microtubule instability, we examined the presence of stable microtubules containing detyrosinated Tubulin by immunofluorescence analysis (Schulze et al 1987;Webster et al 1987;Khawaja et al 1988). Contrary to expectations, no decrease in microtubules with detyrosinated Tubulin was detected in JNK TKO neurons compared with control neurons (Supplemental Fig.…”

Section: Establishment Of Neurons With Compound Jnk Deficiency In Vitromentioning

confidence: 99%

JNK regulates FoxO-dependent autophagy in neurons

Xu¹,

Das²,

Reilly³

et al. 2011

Genes Dev.

201

176

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The cJun N-terminal kinase (JNK) signal transduction pathway is implicated in the regulation of neuronal function. JNK is encoded by three genes that play partially redundant roles. Here we report the creation of mice with targeted ablation of all three Jnk genes in neurons. Compound JNK-deficient neurons are dependent on autophagy for survival. This autophagic response is caused by FoxO-induced expression of Bnip3 that displaces the autophagic effector Beclin-1 from inactive Bcl-XL complexes. These data identify JNK as a potent negative regulator of FoxO-dependent autophagy in neurons.

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“…Such data on the scattering and the reclustering of the Golgi complex have led to the view that Golgi membranes undergo an intimate relationship with MTs and especially with a population of nocodazole-resistant, stable MTs. Stable MTs are characterized by the occurrence of posttranslationally modified tubulin-especially detyrosinated and acetylated tubulin (for review, see MacRae, 1997), which is thought to accumulate in stable MTs because of their longer half-lives, but does not influence MT stability in vivo (Schulze et al, 1987;Khawaja et al, 1988;Webster et al, 1990). Interestingly, not only MT stability influences Golgi localization, but Golgi membranes may reciprocally influence MT stabilization.…”

Section: Introductionmentioning

confidence: 99%

The Golgi Complex Is a Microtubule-organizing Organelle

Chabin-Brion

Marceiller

Perez

et al. 2001

MBoC

277

245

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We show that the Golgi complex can directly stimulate microtubule nucleation in vivo and in vitro and thus behaves as a potent microtubule-organizing organelle in interphase cells. With the use of nocodazole wash-out experiments in hepatic cells, we found that the occurrence of noncentrosomal, early stabilized microtubules is highly correlated with the subcellular localization of Golgi membranes. With the use of in vitro reconstituted microtubule assembly systems with or without cytosol, we also found that, in contrast to centrosomally attached microtubules, the distal ends of Golgi-attached microtubules are remotely stabilized in a way that requires additional cytosolic component (s). Finally, we demonstrate that Golgi-based microtubule nucleation is direct and involves a subset of ␥-tubulin bound to the cytoplasmic face of the organelle. INTRODUCTIONIn interphase cells, the microtubule (MT) network plays a major role in membrane dynamics and organelle localization. In this context, the interaction between the Golgi complex and the MT network has been extensively studied. The Golgi apparatus colocalizes with the minus ends of MTs, which are usually associated with the centrosome (for review see Kreis et al., 1997;Thyberg and Moskalewski, 1999). This localization actually results from an equilibrium between two contradictory movements that have been unraveled with the use of MT-depolymerizing drugs and probably occur on MT subpopulations with different dynamics. The dispersal of Golgi elements occurs along stable MTs after depolymerization of the most labile MT population (Minin, 1997), whereas their reclustering involves newly assembled MTs (Ho et al., 1989). These contradictory movements of Golgi elements are mediated by distinct molecular motors. Consistent with earlier findings by Feiguin et al. (1994), who found that the expression of kinesin antisense oligonucleotide rendered the Golgi apparatus more compact, microinjection of antikinesin antibodies inhibited Golgi dispersion along stable, nocodazole-resistant MTs (Minin, 1997). Conversely, the central localization of the Golgi apparatus involves cytoplasmic dynein (Corthésy-Theulaz et al., 1992;Fath et al., 1994;Burkhardt et al., 1997;Harada et al., 1998). It is also worth noting that, in addition to the kinesin-mediated disruption of the central Golgi complex during MT depolymerization, the dispersion of Golgi elements also relies on the reconstitution of mini Golgi stacks at endoplasmic reticulum (ER) exit sites (Cole et al., 1996;Storrie et al., 1998). Such data on the scattering and the reclustering of the Golgi complex have led to the view that Golgi membranes undergo an intimate relationship with MTs and especially with a population of nocodazole-resistant, stable MTs. Stable MTs are characterized by the occurrence of posttranslationally modified tubulin-especially detyrosinated and acetylated tubulin (for review, see MacRae, 1997), which is thought to accumulate in stable MTs because of their longer half-lives, but does not influence MT stability i...

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Posttranslational modification and microtubule stability.

Cited by 354 publications

References 25 publications

Tau is essential to β-amyloid-induced neurotoxicity

Tau is essential to β-amyloid-induced neurotoxicity

JNK regulates FoxO-dependent autophagy in neurons

The Golgi Complex Is a Microtubule-organizing Organelle

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