Erratum: Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Aβ ligation to β1-integrin conformers

Woo, Jung A.; Zhao, X; Khan, Hirah; Penn, C; Wang, X; Joly-Amado, A; Weeber, E; Morgan, D; Kang, David E.

doi:10.1038/cdd.2015.41

Cited by 23 publications

(39 citation statements)

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“…Therefore, we assessed whether PLD1 can protect against cofilin and Aβ42 O -induced cell death. The mouse hippocampus-derived HT22 neuroblastoma cells have previously been characterized for oligomeric Aβ42-induced neurotoxicity, mitochondrial dysfunction, and apoptosis 1 . We transfected HT22 with control vector (mRFP or EGFP) or cofilin-S3A (mRFP or EGFP fusion variants) with or without PLD1, followed by treatment with or without 1 μM Aβ42 O and/or carbachol (1 mM) for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, Aβ accumulation contributes to neurodegeneration in part via activating apoptotic proteins to induce mitochondrial dysfunction. Our previous study showed that Aβ-induced mitochondrial dysfunction is mediated by Slingshot-1 homolog (SSH1)-dependent activation of cofilin, which leads to the translocation of cofilin to mitochondria 1 , 2 . As a member of a family of actin-binding protein, cofilin plays an essential role in the cytoskeletal dynamics and signaling via its F-actin severing activity.…”

Section: Introductionmentioning

confidence: 99%

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Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation

Liu

Wang

LePochat

et al. 2017

Sci Rep

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Amyloid β (Aβ) accumulation is an early event in the pathogenesis of Alzheimer’s disease (AD), leading to mitochondrial and synaptic dysfunction, tau accumulation, and eventual neuronal death. While the p53 apoptotic pathway has clearly been associated with Aβ deposits and neuronal apoptosis, the critical upstream factors contributing to p53 activation in AD are not well understood. We have previously shown that cofilin activation plays a pivotal role in Aβ-induced mitochondrial and synaptic dysfunction. In this study, we show that activated cofilin (S3A) preferentially forms a complex with p53 and promotes its mitochondrial and nuclear localization, resulting in transcription of p53-responsive genes and promotion of apoptosis. Conversely, reduction of endogenous cofilin by knockdown or genetic deficiency inhibits mitochondrial and nuclear translocation of p53 in cultured cells and in APP/PS1 mice. This cofilin-p53 pro-apoptotic pathway is subject to negative regulation by PLD1 thorough cofilin inactivation and inhibition of cofilin/p53 complex formation. Finally, activated cofilin is unable to induce apoptosis in cells genetically lacking p53. These findings taken together indicate that cofilin coopts and requires the nuclear and mitochondrial pro-apoptotic p53 program to induce and execute apoptosis, while PLD1 functions in a regulatory multi-brake capacity in this pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation

Liu

Wang

LePochat

et al. 2017

Sci Rep

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“…A large number of possible Aβ receptors have been suggested (Jarosz-Griffiths et al, 2016). Interaction between integrins, a large family of extracellular matrix receptors, and Aβ peptides promote neurotoxicity and inhibition of LTP (Wang et al, 2008), mitochondrial and synaptic dysfunction (Woo et al, 2015), gliosis (Wyssenbach et al, 2016) and oligodendrocyte differentiation Quintela-López et al, 2019). In the developing and adult brain, many integrins are present at high levels at synapses (for review, Park and Goda, 2016).…”

Section: Discussionmentioning

confidence: 99%

Early Effects of Aβ Oligomers on Dendritic Spine Dynamics and Arborization in Hippocampal Neurons

Ortiz-Sanz

Gaminde-Blasco

Valero

et al. 2020

Front. Synaptic Neurosci.

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Alzheimer's disease (AD) is a neurodegenerative disorder that leads to impaired memory and cognitive deficits. Spine loss as well as changes in spine morphology correlates with cognitive impairment in this neurological disorder. Many studies in animal models and ex vivo cultures indicate that amyloid β-peptide (Aβ) oligomers induce synaptic damage early during the progression of the disease. Here, in order to determine the events that initiate synaptic alterations, we acutely applied oligomeric Aβ to primary hippocampal neurons and an ex vivo model of organotypic hippocampal cultures from a mouse after targeted expression of EGFP to allow high-resolution imaging and algorithmbased evaluation of spine changes. Dendritic spines were classified as thin, stubby or mushroom, based on morphology. In vivo, time-lapse imaging showed that the three spine types were relatively stable, although their stability significantly decreased after treatment with Aβ oligomers. Unexpectedly, we observed that the density of total dendritic spines increased in organotypic hippocampal slices treated with Aβ compared to control cultures. Specifically, the fraction of stubby spines significantly increased, while mushroom and thin spines remained unaltered. Pharmacological tools revealed that acute Aβ oligomers induced spine changes through mechanisms involving CaMKII and integrin β1 activities. Additionally, analysis of dendritic complexity based on a 3D reconstruction of the whole neuron morphology showed an increase in the apical dendrite length and branching points in CA1 organotypic hippocampal slices treated with Aβ. In contrast to spines, the morphological changes were affected by integrin β1 but not by CaMKII inhibition. Altogether, these data indicate that the Aβ oligomers exhibit early dual effects by acutely enhancing dendritic complexity and spine density.

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“…Slingshots are a small group of phosphatases that regulate multiple physiological functions, such as axon growth and pathfinding (1)(2)(3), neutrophil chemotaxis (4), innate immune responses (5), and mitosis (6,7), by dephosphorylating cofilin and LIMK 4 to modulate actin dynamics (6). Abnormally increased Slingshot phosphatase activity is found in many human diseases, including cancer (8,9), salmonella-related diseases (10), and Alzheimer's disease (11), as well as vascular diseases such as aortic aneurysms, atherosclerosis, and post-angioplasty restenosis (12,13), which is unsurprising, given their role as an important hub controlling actin dynamics. Reducing Slingshot expression or inhibiting Slingshot activity using small chemical compounds has been suggested as a new strategy for treating these diseases (14,15).…”

mentioning

confidence: 99%

Allosteric modulation of the catalytic VYD loop in Slingshot by its N-terminal domain underlies both Slingshot auto-inhibition and activation

Du¹,

Peng

et al. 2018

Journal of Biological Chemistry

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Slingshots are phosphatases that modulate cytoskeleton dynamics, and their activities are tightly regulated in different physiological contexts. Recently, abnormally elevated Slingshot activity has been implicated in many human diseases, such as cancer, Alzheimer's disease, and vascular diseases. Therefore, Slingshot-specific inhibitors have therapeutic potential. However, an enzymological understanding of the catalytic mechanism of Slingshots and of their activation by actin is lacking. Here, we report that the N-terminal region of human Slingshot2 auto-inhibits its phosphatase activity in a noncompetitive manner. pH-dependent phosphatase assays and leaving-group dependence studies suggested that the N-terminal domain of Slingshot2 regulates the stability of the leaving group of the product during catalysis by modulating the general acid Asp in the catalytic VYD loop. F-actin binding relieved this auto-inhibition and restored the function of the general acid. Limited tryptic digestion and biophysical studies identified large conformational changes in Slingshot2 after the F-actin binding. The dissociation of N-terminal structural elements, including Leu, and the exposure of the loop between α-helix-2 and β-sheet-3 of the phosphatase domain served as the structural basis for Slingshot activation via F-actin binding and via neuregulin stimulation in cells. Moreover, we designed a FlAsH-BRET-based Slingshot2 biosensor whose readout was highly correlated with the phosphatase activities of Slingshot2. Our results reveal the auto-inhibitory mechanism and allosteric activation mechanisms of a human Slingshot phosphatase. They also contribute to the design of new strategies to study Slingshot regulation in various cellular contexts and to screen for new activators/inhibitors of Slingshot activity.

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Erratum: Slingshot-Cofilin activation mediates mitochondrial and synaptic dysfunction via Aβ ligation to β1-integrin conformers

Cited by 23 publications

References 0 publications

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation

Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation

Early Effects of Aβ Oligomers on Dendritic Spine Dynamics and Arborization in Hippocampal Neurons

Allosteric modulation of the catalytic VYD loop in Slingshot by its N-terminal domain underlies both Slingshot auto-inhibition and activation

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