Identification and characterization of the Drosophila tau homolog

Heidary, Gena; Fortini, Mark E.

doi:10.1016/s0925-4773(01)00487-7

Cited by 119 publications

(125 citation statements)

References 22 publications

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“…1 A). This is mediated in part by hyperphosphorylation of endogenous fly tau, which is expressed in the fly retina as well as other tissues (Heidary and Fortini, 2001;Nishimura et al, 2004). Furthermore, although coexpression of PAR-1 and wild-type h-tau synergistically enhanced neurodegeneration, coexpression of h-tau(S2A), in which the PAR-1 phosphorylation sites are rendered nonphosphorylatable, blocked the enhancing effect of PAR-1 (Nishimura et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Wang

Imai²,

Lu³

2007

J. Neurosci.

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Aberrant phosphorylation of tau is associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular mechanisms by which tau phosphorylation is regulated under normal and disease conditions are not well understood. Microtubule affinity regulating kinase (MARK) and PAR-1 have been identified as physiological tau kinases, and aberrant phosphorylation of MARK/PAR-1 target sites in tau has been observed in AD patients and animal models. Here we show that phosphorylation of PAR-1 by the tumor suppressor protein LKB1 is required for PAR-1 activation, which in turn promotes tau phosphorylation in Drosophila. Diverse stress stimuli, such as high osmolarity and overexpression of the human ␤-amyloid precursor protein, can promote PAR-1 activation and tau phosphorylation in an LKB1-dependent manner. These results reveal a new function for the tumor suppressor protein LKB1 in a signaling cascade through which the phosphorylation and function of tau is regulated by diverse signals under physiological and pathological conditions.

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Section: Resultsmentioning

confidence: 99%

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Wang

Imai²,

Lu³

2007

J. Neurosci.

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“…Those results raise the possibility that in Drosophila gravity perception cap cells and their Pyx channels might actively respond to motion and participate in mechanosensory signaling. In addition, cap cells in Drosophila larval chordotonal organs contain numerous aligned microtubules (6,(32)(33)(34), and motility of those microtubules is thought to modulate tension in the chordotonal organ (4). Thus, another possibility is that Pyx channels trigger contraction or microtubule motility in Johnston's organ cap cells to influence gravity signals.…”

Section: Discussionmentioning

confidence: 99%

TRPA channels distinguish gravity sensing from hearing in Johnston's organ

Sun¹,

Liu²,

Ben‐Shahar³

et al. 2009

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

149

169

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Although many animal species sense gravity for spatial orientation, the molecular bases remain uncertain. Therefore, we studied Drosophila melanogaster, which possess an inherent upward movement against gravity-negative geotaxis. Negative geotaxis requires Johnston's organ, a mechanosensory structure located in the antenna that also detects near-field sound. Because channels of the transient receptor potential (TRP) superfamily can contribute to mechanosensory signaling, we asked whether they are important for negative geotaxis. We identified distinct expression patterns for 5 TRP genes; the TRPV genes nanchung and inactive were present in most Johnston's organ neurons, the TRPN gene nompC and the TRPA gene painless were localized to 2 subpopulations of neurons, and the TRPA gene pyrexia was expressed in cap cells that may interact with the neurons. Likewise, mutating specific TRP genes produced distinct phenotypes, disrupting negative geotaxis (painless and pyrexia), hearing (nompC), or both (nanchung and inactive). Our genetic, physiological and behavioral data indicate that the sensory component of negative geotaxis involves multiple TRP genes. The results also distinguish between different mechanosensory modalities and set the stage for understanding how TRP channels contribute to mechanosensation. Drosophila ͉ transient receptor potential ͉ geotaxis T he primary mechanosensory organ that detects gravity in Drosophila appears to be Johnston's organ (1). This organ is located in the second antennal segment. It consists of over 200 scolopidia arrayed in a bowl shape (2), with each scolopidium containing mechanosensory chordotonal neurons and their support cells (3-5) (Fig. 1A). Johnston's organ is well known as a detector of near-field sound (3-6). Air particle displacement vibrates the third antennal segment, deforming the cuticle at the joint between segments 2 and 3 where the sensory units of Johnston's organ attach. It was proposed that the third segment may also be deflected by gravity (7), and the geometry of Johnston's organ suggests it could respond to gravity irrespective of head orientation (2). Indeed, recent work indicates that Johnston's organ can also respond to gravity, as well as to wind (1,8). Thus, Johnston's organ may detect multiple different mechanosensory stimuli, and investigations of specific molecular mechanisms underlying these sensory functions may benefit our understanding of other polymodal sensory structures such as the inner ear and dorsal root ganglion in mammals.Almost 50 years ago, Hirsch and colleagues demonstrated that negative geotaxis is genetically encoded in Drosophila (9, 10). Since then, several genes influencing this behavior have been identified (11-13). However, those genes are expressed in both central and peripheral nervous systems, and the nature of their role in the sensory organ that detects gravity remains unknown. The goal of this work was to identify genes involved in sensory aspects of negative geotaxis and in so doing to obtain genetic data to discriminate...

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“…The pathological interaction between A␤ depositions and NFT formation remains to be elucidated, because none of the AD mouse models carrying abundant amyloid deposits developed NFTs (6, 7, 9-12, 14, 15). Therefore, we were motivated to determine whether accumulation of A␤42 leads to the formation of NFT and͞or PHF structure with fly endogenous protein (41). PHF was not detected by either immunoblotting or electron microscopy in A␤42 fly head tissues.…”

Section: Late-onset Progressive Neurodegeneration Caused By A␤42 But Notmentioning

confidence: 99%

Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila : A potential model for Alzheimer's disease

Iijima

Liu

Chiang

et al. 2004

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

439

441

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Accumulation of amyloid-␤ (A␤) peptides in the brain has been suggested to be the primary event in sequential progression of Alzheimer's disease (AD). Here, we use Drosophila to examine whether expression of either the human A␤40 or A␤42 peptide in the Drosophila brain can induce pathological phenotypes resembling AD. The expression of A␤42 led to the formation of diffused amyloid deposits, age-dependent learning defects, and extensive neurodegeneration. In contrast, expression of A␤40 caused only age-dependent learning defects but did not lead to the formation of amyloid deposits or neurodegeneration. These results strongly suggest that accumulation of A␤42 in the brain is sufficient to cause behavioral deficits and neurodegeneration. Moreover, Drosophila may serve as a model for facilitating the understanding of molecular mechanisms underlying A␤ toxicity and the discovery of novel therapeutic targets for AD. A lzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive decline in memory accompanied by histological changes, including neuronal loss and the formation of neurofibrillary tangles (NFTs) and senile plaques (1). The accumulation of amyloid-␤ (A␤)42 peptide, the major component of senile plaques, has been hypothesized to be the primary event in AD pathogenesis (2, 3). The strongest support for the A␤ hypothesis comes from genetic analyses of familial AD (FAD); most FAD mutations identified in A␤ precursor protein (APP), Presenilin1 (PS1) and Presenilin2 (PS2) genes appear to cause excessive accumulation of A␤42 (4). Secretion of A␤ peptides is a result of sequential cleavage of APP by ␤-secretase, a type I transmembrane glycosylated aspartyl protease, and ␥-secretase, a large protein complex that includes at least four proteins, Presenilins (PS1 or PS2), Nicastrin, Aph-1, and Pen-2 (for review, see ref. 5). The heterogeneity of ␥-secretase cleavage gives rise to a series of A␤ peptides, including the major species A␤40 and a smaller amount of A␤42.To study AD pathogenesis in vivo, a number of AD mouse models have been established and have successfully recapitulated AD-like phenotypes, including abundant amyloid deposits, astroglial activation, synaptic loss and dysfunction, behavioral abnormalities, and neurodegeneration (6-15). In addition to these mouse models, the model systems that allow highthroughput genetic screening will facilitate the discovery of genes involved in AD pathogenesis. Furthermore, one of the intriguing issues that have not been elucidated in these transgenic mice is the pathological roles of each specific A␤ species (i.e., A␤40 and A␤42), because currently available mouse models mainly rely on overexpression of APP.We use a Drosophila model (16) to compare the specific pathological roles of A␤40 and A␤42. In Drosophila, all components involved in the protein complex responsible for ␥-secretase activity are highly conserved (17), whereas ␤-secretase activity is absent or very low (18). An APP-like protein (APPL) is also present in flies, althou...

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Identification and characterization of the Drosophila tau homolog

Cited by 119 publications

References 22 publications

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

TRPA channels distinguish gravity sensing from hearing in Johnston's organ

Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila : A potential model for Alzheimer's disease

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