Novel Neuroprotective Function of Apical-Basal Polarity Gene Crumbs in Amyloid Beta 42 (Aβ42) Mediated Neurodegeneration

Steffensmeier, Andrew M.; Tare, Meghana; Puli, Oorvashi Roy; Modi, Rohan M.; Nainaparampil, Jaison; Kango‐Singh, Madhuri; Singh, Amit

doi:10.1371/journal.pone.0078717

Cited by 27 publications

(37 citation statements)

References 51 publications

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“…Because of the recent discovery of the relationship between the crb and amyoid beta, it may be possible these three genes work together in the same genetic pathway (Steffensmeier et al, 2013). Our data strongly suggests that Tau plays important functions in the modulation of cell membrane domains including the apical Crb and AJs in photoreceptors during pupal eye morphogenesis.…”

Section: Discussionmentioning

confidence: 67%

“…Given the high degree of evolutionary conservation of crb and tau genes from Drosophila to higher mammals including humans, the similar cooperative mechanism between crb and tau could have a role in the development and degeneration of human photoreceptor. Because of the recent discovery of the relationship between the crb and amyoid beta, it may be possible these three genes work together in the same genetic pathway (Steffensmeier et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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Role of Tau, a microtubule associated protein, in Drosophila photoreceptor morphogenesis

Nam

2016

Genesis

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Cell polarity genes have important functions in photoreceptor morphogenesis. Based on recent discovery of stabilized microtubule cytoskeleton in developing photoreceptors and its role in photoreceptor cell polarity, microtubule associated proteins might have important roles in controlling cell polarity proteins' localizations in developing photoreceptors. Here, Tau, a microtubule associated protein, was analyzed to find its potential role in photoreceptor cell polarity. Tau colocalizes with acetylated/stabilized microtubules in developing pupal photoreceptors. Although it is known that tau mutant photoreceptor has no defects in early eye differentiation and development, it shows dramatic disruptions of cell polarity proteins, adherens junctions, and the stable microtubules in developing pupal photoreceptors. This role of Tau in cell polarity proteins' localization in photoreceptor cells during the photoreceptor morphogenesis was further supported by Tau's overexpression studies. Tau overexpression caused dramatic expansions of apical membrane domains where the polarity proteins localize in the developing pupal photoreceptors. It is also found that Tau's role in photoreceptor cell polarity depends on Par-1 kinase. Furthermore, a strong genetic interaction between tau and crumbs was found. It is found that Tau has a crucial role in cell polarity protein localization during pupal photoreceptor morphogenesis stage, but not in early eye development including eye cell differentiation.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Role of Tau, a microtubule associated protein, in Drosophila photoreceptor morphogenesis

Nam

2016

Genesis

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“…Adult Drosophila eye images were taken 70 using a Zeiss Apotome Imager.Z1 microscope (Carl Zeiss Microscopy GmbH, Jena, Germany). The flies were prepared by freezing them at −20 °C for ~2 h. The legs and wings of the flies were removed and flies were mounted on a dissection needle, and the fly was positioned on a glass slide using mounting putty.…”

Section: Methodsmentioning

confidence: 99%

Cullin-4 regulates Wingless and JNK signaling-mediated cell death in the Drosophila eye

et al. 2016

Self Cite

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In all multicellular organisms, the fundamental processes of cell proliferation and cell death are crucial for growth regulation during organogenesis. Strict regulation of cell death is important to maintain tissue homeostasis by affecting processes like regulation of cell number, and elimination of unwanted/unfit cells. The developing Drosophila eye is a versatile model to study patterning and growth, where complex signaling pathways regulate growth and cell survival. However, the molecular mechanisms underlying regulation of these processes is not fully understood. In a gain-of-function screen, we found that misexpression of cullin-4 (cul-4), an ubiquitin ligase, can rescue reduced eye mutant phenotypes. Previously, cul-4 has been shown to regulate chromatin remodeling, cell cycle and cell division. Genetic characterization of cul-4 in the developing eye revealed that loss-of-function of cul-4 exhibits a reduced eye phenotype. Analysis of twin-spots showed that in comparison with their wild-type counterparts, the cul-4 loss-of-function clones fail to survive. Here we show that cul-4 clones are eliminated by induction of cell death due to activation of caspases. Aberrant activation of signaling pathways is known to trigger cell death in the developing eye. We found that Wingless (Wg) and c-Jun-amino-terminal-(NH2)-Kinase (JNK) signaling are ectopically induced in cul-4 mutant clones, and these signals co-localize with the dying cells. Modulating levels of Wg and JNK signaling by using agonists and antagonists of these pathways demonstrated that activation of Wg and JNK signaling enhances cul-4 mutant phenotype, whereas downregulation of Wg and JNK signaling rescues the cul-4 mutant phenotypes of reduced eye. Here we present evidences to demonstrate that cul-4 is involved in restricting Wg signaling and downregulation of JNK signaling-mediated cell death during early eye development. Overall, our studies provide insights into a novel role of cul-4 in promoting cell survival in the developing Drosophila eye.

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“…Identified pathological changes in AD are an increased production of senile plaques, an accumulation of b-amyloid (Ab) protein generated by endoproteolytic cleavage of a 42 amino acid peptide with a high propensity of aggregation, reactive microglial cells, dystrophic neurites and bundles of astrocytic processes and intracellular neurofibrillary tangles 86,87 . The accumulation of b-amyloid protein leads to extensive neuronal degeneration and triggers neuronal cell death by unknown mechanism 88 . There is currently no cure for AD and, although available medications may temporarily ease symptoms, they do not slow the progression.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Nanoneurotherapeutics approach intended for direct nose to brain delivery

Shadab

Mustafa

Baboota

et al. 2015

Drug Development and Industrial Pharmacy

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This review highlights the understanding of several brain diseases and the important pathophysiological mechanisms involved. The review discusses the role of nanotherapeutics in treating brain disorders via nose to brain delivery, the mechanisms of drug absorption across nasal mucosa to the brain, strategies to overcome the blood brain barrier, nanoformulation strategies for enhanced brain targeting via nasal route and neurotoxicity issues of nanoparticles.

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Novel Neuroprotective Function of Apical-Basal Polarity Gene Crumbs in Amyloid Beta 42 (Aβ42) Mediated Neurodegeneration

Cited by 27 publications

References 51 publications

Role of Tau, a microtubule associated protein, in Drosophila photoreceptor morphogenesis

Role of Tau, a microtubule associated protein, in Drosophila photoreceptor morphogenesis

Cullin-4 regulates Wingless and JNK signaling-mediated cell death in the Drosophila eye

Nanoneurotherapeutics approach intended for direct nose to brain delivery

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