Upregulation of Proteolytic Pathways and Altered Protein Biosynthesis Underlie Retinal Pathology in a Mouse Model of Alzheimer’s Disease

Mirzaei, Mehdi; Pushpitha, Kanishka; Deng, Lei; Chitranshi, Nitin; Gupta, Veer Bala; Rajput, Rashi; Mangani, Abu Bakr; Dheer, Yogita; Godinez, Angela; McKay, Matthew J.; Kamath, Karthik Shantharam; Pascovici, Dana; Wu, Jemma X.; Salekdeh, Ghasem Hosseini; Karl, Tim; Haynes, Paul A.; Graham, Stuart L.; Gupta, Vivek Kumar

doi:10.1007/s12035-019-1479-4

Cited by 48 publications

(66 citation statements)

References 71 publications

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“…The retinas of experimental glaucoma (n = 5) and control animals (n = 5) were extracted from the eyes using the surgical microscope. Protein extraction was carried out using lysis buffer (20 mM 4‐(2‐hydroxyethyl)‐1‐piperazineethanesulfonic acid, pH 7.4, 1% Triton X‐100, and 1 mM ethylenediaminetetraacetic acid) containing protease and phosphatase inhibitors 18 . Samples were subjected to probe sonication (three pulses per 15 seconds with 20 seconds between each pulse).…”

Section: Methodsmentioning

confidence: 99%

“…Protein extraction was carried out using lysis buffer (20 mM 4-(2-hydroxyethyl)-1piperazineethanesulfonic acid, pH 7.4, 1% Triton X-100, and 1 mM ethylenediaminetetraacetic acid) containing protease and phosphatase inhibitors. 18 Samples were subjected to probe sonication (three pulses per 15 seconds with 20 seconds between each pulse). Lysed samples were centrifuged (15 000g for 10 minutes at 4°C) and protein in the supernatant concentrated by precipitation using a chloroform-methanol precipitation procedure.…”

Section: Preparation Of Protein Samplesmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Preparation Of Protein Samplesmentioning

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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“…Proteolytic imbalance of cell cycle regulators can for instance hamper signalling pathways essential for axonal guidance and neural wiring [ 32 ]. Altered proteolytic cleavage and post translational events may also cause toxic accumulation of protein aggregates in cells [ 33 , 34 ]. Protein aggregates such as TDP-43 and C9ORF72 repeats in amyotrophic lateral sclerosis (ALS) [ 35 ], polyQ-expanded huntingtin in HD [ 36 ], hypo-phosphorylated tau and amyloid β in AD [ 37 ], α-synuclein in parkinson's disease (PD) [ 38 ] are generally removed via proteasomal machinery but excessive toxic overload of aggregates may expose cells to persistent oxidative stress.…”

Section: Factors Triggering Cell Cycle Activation In Neuronsmentioning

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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“…RPL26 staining was reduced in neurons of layer II of the entorhinal cortex in ADD patients [53]. RPL35A was reduced in the retina of aged APP/PS1 (ADD-like) mice [54]. By comparing blood and brain transcriptomes in a systematic analysis, an RNA signature comprising NDUFA1 , MRPL51 , and RPL36AL discriminated between ADD patients and controls with high sensitivity and specificity [55].…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of Gene Expression Changes in the Blood of Patients with Mild Cognitive Impairment and Alzheimer’s Disease Dementia

Bottero

Potashkin

2019

IJMS

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Background: Dementia is a major public health concern affecting approximately 47 million people worldwide. Mild cognitive impairment (MCI) is one form of dementia that affects an individual’s memory with or without affecting their daily life. Alzheimer’s disease dementia (ADD) is a more severe form of dementia that usually affects elderly individuals. It remains unclear whether MCI is a distinct disorder from or an early stage of ADD. Methods: Gene expression data from blood were analyzed to identify potential biomarkers that may be useful for distinguishing between these two forms of dementia. Results: A meta-analysis revealed 91 genes dysregulated in individuals with MCI and 387 genes dysregulated in ADD. Pathway analysis identified seven pathways shared between MCI and ADD and nine ADD-specific pathways. Fifteen transcription factors were associated with MCI and ADD, whereas seven transcription factors were specific for ADD. Mir-335-5p was specific for ADD, suggesting that it may be useful as a biomarker. Diseases that are associated with MCI and ADD included developmental delays, cognition impairment, and movement disorders. Conclusion: These results provide a better molecular understanding of peripheral changes that occur in MCI and ADD patients and may be useful in the identification of diagnostic and prognostic biomarkers.

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Upregulation of Proteolytic Pathways and Altered Protein Biosynthesis Underlie Retinal Pathology in a Mouse Model of Alzheimer’s Disease

Cited by 48 publications

References 71 publications

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

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

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

Meta-Analysis of Gene Expression Changes in the Blood of Patients with Mild Cognitive Impairment and Alzheimer’s Disease Dementia

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