Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

Chitranshi, Nitin; Dheer, Yogita; Mirzaei, Mehdi; Wu, Yunqi; Salekdeh, Ghasem Hosseini; Abbasi, Mojdeh; Gupta, Veer Bala; Wall, Roshana Vander; You, Yuyi; Graham, Stuart L.; Gupta, Vivek Kumar

doi:10.1016/j.ymthe.2018.09.019

Cited by 47 publications

(40 citation statements)

References 72 publications

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“…After high pH reversed-phase peptide fractionation, peptides were consolidated into 16 fractions. Dried fractions were resuspended in 1% formic acid, and then desalted again using SDB-RPS (3 M-Empore) stage tips (Chitranshi et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

Amyloid β Induces Early Changes in the Ribosomal Machinery, Cytoskeletal Organization and Oxidative Phosphorylation in Retinal Photoreceptor Cells

Deng

Pushpitha

Joseph

et al. 2019

Front. Mol. Neurosci.

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Amyloid β (Aβ) accumulation and its aggregation is characteristic molecular feature of the development of Alzheimer’s disease (AD). More recently, Aβ has been suggested to be associated with retinal pathology associated with AD, glaucoma and drusen deposits in age related macular degeneration (AMD). In this study, we investigated the proteins and biochemical networks that are affected by Aβ in the 661 W photoreceptor cells in culture. Time and dose dependent effects of Aβ on the photoreceptor cells were determined utilizing tandem mass tag (TMT) labeling-based quantitative mass-spectrometric approach. Bioinformatic analysis of the data revealed concentration and time dependent effects of the Aβ peptide stimulation on various key biochemical pathways that might be involved in mediating the toxicity effects of the peptide. We identified increased Tau phosphorylation, GSK3β dysregulation and reduced cell viability in cells treated with Aβ in a dose and time dependent manner. This study has delineated for the first-time molecular networks in photoreceptor cells that are impacted early upon Aβ treatment and contrasted the findings with a longer-term treatment effect. Proteins associated with ribosomal machinery homeostasis, mitochondrial function and cytoskeletal organization were affected in the initial stages of Aβ exposure, which may provide key insights into AD effects on the photoreceptors and specific molecular changes induced by Aβ peptide.

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Section: Methodsmentioning

confidence: 99%

Amyloid β Induces Early Changes in the Ribosomal Machinery, Cytoskeletal Organization and Oxidative Phosphorylation in Retinal Photoreceptor Cells

Deng

Pushpitha

Joseph

et al. 2019

Front. Mol. Neurosci.

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“…E2F can be another candidate for gene targeting as E2F transcription factor decoy was indeed shown to modulate cell cycle progression in rat glomerular cells in vivo [ 205 ]. Various growth factors and activation of their receptors as well as phosphatases and kinases regulating their downstream signalling have been extensively shown to modulate cellular survival and cell cycle events and could be promising gene therapy targets [ 206 - 208 ]. These genetic modulation approaches will help in specific targeting of cell cycle regulatory proteins to develop mechanism-based therapeutics and help understand the molecular basis of downstream events of cell cycle dysregulation.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development

Joseph¹,

Mangani²,

Gupta³

et al. 2020

Aging and disease

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Cell cycle dysregulation has been implicated in the pathogenesis of neurodegenerative disorders. Specialised function obligates neuronal cells to subsist in a quiescent state of cell cycle once differentiated and therefore the circumstances and mechanisms underlying aberrant cell cycle activation in post-mitotic neurons in physiological and disease conditions remains an intriguing area of research. There is a strict requirement of concurrence to cell cycle regulation for neurons to ensure intracellular biochemical conformity as well as interrelationship with other cells within neural tissues. This review deliberates on various mechanisms underlying cell cycle regulation in neuronal cells and underscores potential implications of their non-compliance in neural pathology. Recent research suggests that successful duplication of genetic material without subsequent induction of mitosis induces inherent molecular flaws that eventually assert as apoptotic changes. The consequences of anomalous cell cycle activation and subsequent apoptosis are demonstrated by the increased presence of molecular stress response and apoptotic markers. This review delineates cell cycle events under normal physiological conditions and deficits amalgamated by alterations in protein levels and signalling pathways associated with cell-division are analysed. Cell cycle regulators essentially, cyclins, CDKs, cip/kip family of inhibitors, caspases, bax and p53 have been identified to be involved in impaired cell cycle regulation and associated with neural pathology. The pharmacological modulators of cell cycle that are shown to impart protection in various animal models of neurological deficits are summarised. Greater understanding of the molecular mechanisms that are indispensable to cell cycle regulation in neurons in health and disease conditions will facilitate targeted drug development for neuroprotection.

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“…An experimental glaucoma model was established by producing a chronic increase of IOP in mice by microbead (Fluospheres; Molecular Probes; 10 μm) injections in the anterior chamber as reported previously. [13][14][15][16] Intraocular injections (3.6 × 10 6 microbeads/mL) in the anterior chamber of the eye were performed until a sustained increase in IOP was observed. Eyes were injected using a 25-μL Hamilton syringe connected to a disposable 33-gauge needle (TSK, Japan).…”

Section: Intraocular Injections and Pressure Measurementsmentioning

confidence: 99%

Retinal proteomics of experimental glaucoma model reveal intraocular pressure‐induced mediators of neurodegenerative changes

Mirzaei

Gupta

Chitranshi

et al. 2020

J of Cellular Biochemistry

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Current evidence suggests that exposure to chronically induced intraocular pressure (IOP) leads to neurodegenerative changes in the inner retina. This study aimed to determine retinal proteomic alterations in a rat model of glaucoma and compared findings with human retinal proteomics changes in glaucoma reported previously. We developed an experimental glaucoma rat model by subjecting the rats to increased IOP (9.3 ± 0.1 vs 20.8 ± 1.6 mm Hg) by weekly microbead injections into the eye (8 weeks). The retinal tissues were harvested from control and glaucomatous eyes and protein expression changes analysed using a multiplexed quantitative proteomics approach (TMT-MS3). Immunofluorescence was performed for selected protein markers for data validation. Our study identified 4304 proteins in the rat retinas. Out of these, 139 proteins were downregulated (≤0.83) while the expression of 109 proteins was upregulated (≥1.2-fold change) under glaucoma conditions (P ≤ .05). Computational analysis revealed reduced expression of proteins associated with glutathione metabolism, mitochondrial dysfunction/oxidative phosphorylation, cytoskeleton, and actin filament organisation, along with increased expression of proteins in coagulation cascade, apoptosis, oxidative stress, and RNA processing. Further functional network analysis highlighted the differential modulation of nuclear receptor signalling, cellular survival, protein synthesis, transport, and cellular assembly pathways. Alterations in crystallin family, glutathione metabolism, and mitochondrial dysfunction associated proteins shared similarities between the animal model of glaucoma and the human disease condition. In contrast, the activation of the classical complement pathway and upregulation of cholesterol transport proteins were exclusive to human glaucoma. These findings provide insights into the Mehdi Mirzaei, Vivek K. Gupta, and Nitin Chitranshi contributed equally to this study. neurodegenerative mechanisms that are specifically affected in the retina in response to chronically elevated IOP.

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Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection

Cited by 47 publications

References 72 publications

Amyloid β Induces Early Changes in the Ribosomal Machinery, Cytoskeletal Organization and Oxidative Phosphorylation in Retinal Photoreceptor Cells

Amyloid β Induces Early Changes in the Ribosomal Machinery, Cytoskeletal Organization and Oxidative Phosphorylation in Retinal Photoreceptor Cells

Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development

Retinal proteomics of experimental glaucoma model reveal intraocular pressure‐induced mediators of neurodegenerative changes

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