Activation of JNK Signaling Mediates Amyloid-ß-Dependent Cell Death

Tare, Meghana; Modi, Rohan M.; Nainaparampil, Jaison; Puli, Oorvashi Roy; Bedi, Shimpi; Fernández-Fúnez, Pedro; Kango‐Singh, Madhuri; Singh, Amit

doi:10.1371/journal.pone.0024361

Cited by 74 publications

(160 citation statements)

References 59 publications

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“…A similar analysis on HhC expressed in photoreceptor neurons ( GMR-Gal4 ; Fig. 3A,D, white bars and ; Tare et al, 2011) showed a larger disparity between anterograde and retrograde transport, with the velocities calculated at 0.50 and 0.17 µm s −1 , respectively. The ranges of velocities strongly suggest that Hh is trafficked within motor neuron and photoreceptor axons via microtubule-based fast axonal transport and that kinesin and dynein are its primary molecular motors (Goldstein and Yang, 2000).…”

Section: Resultssupporting

confidence: 59%

Analysis of axonal trafficking via a novel live imaging technique reveals distinct Hedgehog transport kinetics

2017

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The Drosophila melanogaster (Dmel) eye is an ideal model to study development, intracellular signaling, behavior, and neurodegenerative disease. Interestingly, dynamic data are not commonly employed to investigate eye-specific disease models. Using axonal transport of the morphogen Hedgehog (Hh), which is integral to Dmel eye-brain development and implicated in stem cell maintenance and neoplastic disease, we demonstrate the ability to comprehensively quantify and characterize its trafficking in various neuron types and a neurodegeneration model in live early third-instar larval Drosophila. We find that neuronal Hh, whose kinetics have not been reported previously, favors fast anterograde transport and varies in speed and flux with respect to axonal position. This suggests distinct trafficking pathways along the axon. Lastly, we report abnormal transport of Hh in an accepted model of photoreceptor neurodegeneration. As a technical complement to existing eye-specific disease models, we demonstrate the ability to directly visualize transport in real time in intact and live animals and track secreted cargoes from the axon to their release points. Particle dynamics can now be precisely calculated and we posit that this method could be conveniently applied to characterizing disease pathogenesis and genetic screening in other established models of neurodegeneration.

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Section: Resultssupporting

confidence: 59%

Analysis of axonal trafficking via a novel live imaging technique reveals distinct Hedgehog transport kinetics

2017

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“…The robust eye phenotype in flies expressing Aβ42 is due, in part, to massive cell death that starts soon after the expression of Aβ42 (30). We next examined the ability of secHsp70 to suppress the Aβ42-induced cell death in the developing eye.…”

Section: Resultsmentioning

confidence: 99%

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Fernández-Fúnez

Sanchez-Garcia

Mena

et al. 2016

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

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Alzheimer’s disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

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“…Accumulation of Aβ42 triggers aberrant signaling mechanism(s) and impairs the basic cellular processes leading to the death of neurons in the developing neural retina of pupa and the adult eye ( Figure 1, Table 1) [26]. However, the genetic basis of Aβ42 mediated neurodegeneration has not been fully understood.…”

Section: Resultsmentioning

confidence: 99%

“…The P-values were calculated using one-tailed t -test and the error bars represent Standard Deviation from Mean [26]. …”

Section: Methodsmentioning

confidence: 99%

Homeotic Gene teashirt (tsh) Has a Neuroprotective Function in Amyloid-Beta 42 Mediated Neurodegeneration

et al. 2013

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BackgroundAlzheimer's disease (AD) is a debilitating age related progressive neurodegenerative disorder characterized by the loss of cognition, and eventual death of the affected individual. One of the major causes of AD is the accumulation of Amyloid-beta 42 (Aβ42) polypeptides formed by the improper cleavage of amyloid precursor protein (APP) in the brain. These plaques disrupt normal cellular processes through oxidative stress and aberrant signaling resulting in the loss of synaptic activity and death of the neurons. However, the detailed genetic mechanism(s) responsible for this neurodegeneration still remain elusive.Methodology/ Principle FindingsWe have generated a transgenic Drosophila eye model where high levels of human Aβ42 is misexpressed in the differentiating photoreceptor neurons of the developing eye, which phenocopy Alzheimer's like neuropathology in the neural retina. We have utilized this model for a gain of function screen using members of various signaling pathways involved in the development of the fly eye to identify downstream targets or modifiers of Aβ42 mediated neurodegeneration. We have identified the homeotic gene teashirt (tsh) as a suppressor of the Aβ42 mediated neurodegenerative phenotype. Targeted misexpression of tsh with Aβ42 in the differentiating retina can significantly rescue neurodegeneration by blocking cell death. We found that Tsh protein is absent/ downregulated in the neural retina at this stage. The structure function analysis revealed that the PLDLS domain of Tsh acts as an inhibitor of the neuroprotective function of tsh in the Drosophila eye model. Lastly, we found that the tsh paralog, tiptop (tio) can also rescue Aβ42 mediated neurodegeneration.Conclusions/SignificanceWe have identified tsh and tio as new genetic modifiers of Aβ42 mediated neurodegeneration. Our studies demonstrate a novel neuroprotective function of tsh and its paralog tio in Aβ42 mediated neurodegeneration. The neuroprotective function of tsh is independent of its role in retinal determination.

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Activation of JNK Signaling Mediates Amyloid-ß-Dependent Cell Death

Cited by 74 publications

References 59 publications

Analysis of axonal trafficking via a novel live imaging technique reveals distinct Hedgehog transport kinetics

Analysis of axonal trafficking via a novel live imaging technique reveals distinct Hedgehog transport kinetics

Holdase activity of secreted Hsp70 masks amyloid-β42 neurotoxicity in Drosophila

Homeotic Gene teashirt (tsh) Has a Neuroprotective Function in Amyloid-Beta 42 Mediated Neurodegeneration

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