Proteomic Analysis Identifies Dysfunction in Cellular Transport, Energy, and Protein Metabolism in Different Brain Regions of Atypical Frontotemporal Lobar Degeneration

2012 ◽  
Vol 11 (4) ◽  
pp. 2533-2543 ◽  
Author(s):  
Daniel Martins-de-Souza ◽  
Paul C. Guest ◽  
David M. Mann ◽  
Sigrun Roeber ◽  
Hassan Rahmoune ◽  
...  
Keyword(s):  
Protein Metabolism ◽  
Proteomic Analysis ◽  
Frontotemporal Lobar Degeneration ◽  
Brain Regions ◽  
Cellular Transport

scholarly journals Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

2021 ◽  
Author(s):  
Rahat Hasan ◽  
Jack Humphrey ◽  
Conceicao Bettencourt ◽  
Tammaryn Lashley ◽  
Pietro Fratta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Frontotemporal Lobar Degeneration ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Temporal Cortex ◽  
Neuronal Loss ◽  
Underlying Disease ◽  
Brain Regions ◽  
Neuronal Markers ◽  
The Brain

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

Proteomic analysis of diaminochlorotriazine (DACT) adducts in three brain regions of Wistar Rats

2010 ◽  
Vol 199 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Gregory P. Dooley ◽  
Amanda K. Ashley ◽  
Marie E. Legare ◽  
Robert J. Handa ◽  
William H. Hanneman
Keyword(s):  
Proteomic Analysis ◽  
Wistar Rats ◽  
Brain Regions

scholarly journals Comparative Proteomic Analysis of Coregulation of CIPK14 and WHIRLY1/3 Mediated Pale Yellowing of Leaves in Arabidopsis

2018 ◽  
Vol 19 (8) ◽  
pp. 2231 ◽  
Author(s):  
Zhe Guan ◽  
Wanzhen Wang ◽  
Xingle Yu ◽  
Wenfang Lin ◽  
Ying Miao
Keyword(s):  
Protein Metabolism ◽  
Proteomic Analysis ◽  
Photochemical Efficiency ◽  
Time Of Flight ◽  
Photochemical Quenching ◽  
Relative Distribution ◽  
Ribulose Bisphosphate Carboxylase ◽  
Ribulose Bisphosphate ◽  
Ps Ii ◽  
Bisphosphate Carboxylase

Pale yellowing of leaf variegation is observed in the mutant Arabidopsis lines Calcineurin B-Like-Interacting Protein Kinase14 (CIPK14) overexpression (oeCIPK14) and double-knockout WHIRLY1/WHIRLY3 (why1/3). Further, the relative distribution of WHIRLY1 (WHY1) protein between plastids and the nucleus is affected by the phosphorylation of WHY1 by CIPK14. To elucidate the coregulation of CIPK14 and WHIRLY1/WHIRLY3-mediated pale yellowing of leaves, a differential proteomic analysis was conducted between the oeCIPK14 variegated (oeCIPK14-var) line, why1/3 variegated (why1/3-var) line, and wild type (WT). More than 800 protein spots were resolved on each gel, and 67 differentially abundant proteins (DAPs) were identified by matrix-assisted laser desorption ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF-MS). Of these 67 proteins, 34 DAPs were in the oeCIPK14-var line and 33 DAPs were in the why1/3-var line compared to the WT. Five overlapping proteins were differentially expressed in both the oeCIPK14-var and why1/3-var lines: ATP-dependent Clp protease proteolytic subunit-related protein 3 (ClpR3), Ribulose bisphosphate carboxylase large chain (RBCL), Beta-amylase 3 (BAM3), Ribosome-recycling factor (RRF), and Ribulose bisphosphate carboxylase small chain (RBCS). Bioinformatics analysis showed that most of the DAPs are involved in photosynthesis, defense and antioxidation pathways, protein metabolism, amino acid metabolism, energy metabolism, malate biosynthesis, lipid metabolism, and transcription. Thus, in the why1/3-var and oeCIPK14-var lines, there was a decrease in the photosystem parameters, including the content of chlorophyll, the photochemical efficiency of photosystem (PS II) (Fv/Fm), and electron transport rates (ETRs), but there was an increase in non-photochemical quenching (NPQ). Both mutants showed high sensitivity to intense light. Based on the annotation of the DAPs from both why1/3-var and oeCIPK14-var lines, we conclude that the CIPK14 phosphorylation-mediated WHY1 deficiency in plastids is related to the impairment of protein metabolism, leading to chloroplast dysfunction.

scholarly journals Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

2021 ◽  
Author(s):  
Rahat Hasan ◽  
Jack Humphrey ◽  
Conceição Bettencourt ◽  
Jia Newcombe ◽  
Tammaryn Lashley ◽  
...  
Keyword(s):  
Frontotemporal Lobar Degeneration ◽  
Brain Regions ◽  
Transcriptomic Analysis ◽  
Cellular Alterations

scholarly journals Suppression of Progranulin Expression Leads to Formation of Intranuclear TDP-43 Inclusions In Vitro: A Cell Model of Frontotemporal Lobar Degeneration

2019 ◽  
Vol 78 (12) ◽  
pp. 1124-1129
Author(s):  
Jiuling Zhu ◽  
Ning Wang ◽  
Xianan Li ◽  
Xiaojing Zheng ◽  
Junli Zhao ◽  
...  
Keyword(s):  
Cell Line ◽  
Frontotemporal Lobar Degeneration ◽  
Cell Model ◽  
Neuroblastoma Cell ◽  
Brain Regions ◽  
Neuroblastoma Cell Line ◽  
Null Alleles ◽  
Intranuclear Inclusions ◽  
A Cell

Abstract Mutations in the GRN gene coding for progranulin (PGRN) are responsible for many cases of familial frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein 43 (TDP-43)-positive inclusions (FTLD-TDP). GRN mutations create null alleles resulting in decreased progranulin protein or haploinsufficiency. FTLD-TDP with GRN mutations is characterized by lentiform neuronal intranuclear inclusions that are positive for TDP-43 in affected brain regions. In this study, by stably expressed short hairpin RNA, we established a neuroblastoma cell line with decreased PGRN level. This cell line reveals TDP-43-positive intranuclear inclusions. In addition, replacement with purified PGRN protein restores normal TDP-43 nuclear distribution. This cell model can be valuable for the study of the role of PGRN in the pathogenesis in FTLD-TDP.

scholarly journals Proteomic Analysis of Brain Regions Reveals Brain Regional Differences and the Involvement of Multiple Keratins in Chronic Alcohol Neurotoxicity

2020 ◽  
Vol 55 (2) ◽  
pp. 147-156
Author(s):  
Dingang Zhang ◽  
Xiaoru Dong ◽  
Xiaochen Liu ◽  
Lin Ye ◽  
Shuhao Li ◽  
...  
Keyword(s):  
Proteomic Analysis ◽  
Regional Differences ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Alcohol Intoxication ◽  
Expression Patterns ◽  
Alcohol Exposure ◽  
Brain Regions ◽  
Chronic Alcohol ◽  
Public Attention

Abstract Aims Alcohol abuse has attracted public attention and chronic alcohol exposure can result in irreversible structural changes in the brain. The molecular mechanisms underlying alcohol neurotoxicity are complex, mandating comprehensive mining of spatial protein expression profile. Methods In this study, mice models of chronic alcohol intoxication were established after 95% alcohol vapor administration for 30 consecutive days. On Day 30, striatum (the dorsal and ventral striatum) and hippocampus, the two major brain regions responsible for learning and memorizing while being sensitive to alcohol toxicity, were collected. After that, isobaric tags for relative and absolute quantitation -based quantitative proteomic analysis were carried out for further exploration of the novel mechanisms underlying alcohol neurotoxicity. Results Proteomic results showed that in the striatum, 29 proteins were significantly up-regulated and 17 proteins were significantly down-regulated. In the hippocampus, 72 proteins were significantly up-regulated, while 2 proteins were significantly down-regulated. Analysis of the overlay proteins revealed that a total of 102 proteins were consistently altered (P < 0.05) in both hippocampus and striatum regions, including multiple keratins such as Krt6a, Krt17 and Krt5. Ingenuity pathway analysis revealed that previously reported diseases/biofunctions such as dermatological diseases and developmental disorders were enriched in those proteins. Interestingly, the glucocorticoid receptor (GR) signaling was among the top enriched pathways in both brain regions, while multiple keratins from the GR signaling such as Krt1 and Krt17 exhibited significantly opposite expression patterns in the two brain nuclei. Moreover, there are several other involved pathways significantly differed between the hippocampus and striatum. Conclusions Our data revealed brain regional differences upon alcohol consumption and indicated the critical involvement of keratins from GR signaling in alcohol neurotoxicity. The differences in proteomic results between the striatum and hippocampus suggested a necessity of taking into consideration brain regional differences and intertwined signaling pathways rather than merely focusing on single nuclei or molecule during the study of drug-induced neurotoxicity in the future.

scholarly journals Proteomic analysis reveals changes in carbohydrate and protein metabolism associated with broiler breast myopathy

2017 ◽  
Vol 96 (8) ◽  
pp. 2992-2999 ◽  
Author(s):  
Vivek A. Kuttappan ◽  
Walter Bottje ◽  
Ranjith Ramnathan ◽  
Steven D. Hartson ◽  
Craig N. Coon ◽  
...  
Keyword(s):  
Protein Metabolism ◽  
Proteomic Analysis ◽  
Broiler Breast

scholarly journals A Practical Approach to Differentiate the Frontotemporal Tauopathy Subtypes

2020 ◽  
Vol 79 (10) ◽  
pp. 1122-1126
Author(s):  
Shelley L Forrest ◽  
Glenda M Halliday ◽  
Anastasia Sizemova ◽  
Marloes van Roijen ◽  
Ciara V McGinley ◽  
...  
Keyword(s):  
Frontotemporal Lobar Degeneration ◽  
Interrater Reliability ◽  
Corticobasal Degeneration ◽  
Brain Regions ◽  
Practical Approach ◽  
Perfect Agreement ◽  
Minimum Number ◽  
Globular Glial Tauopathy ◽  
Pick Disease ◽  
Neuropathological Criteria

Abstract This study proposes a practical approach, using the minimum number of brain regions and stains, to consolidate previously published neuropathological criteria into one operationalized schema to differentiate subtypes of frontotemporal lobar degeneration with tau-immunopositive inclusions (FTLD-tau). This approach uses the superior frontal and precentral cortices and hippocampus stained for phosphorylated-tau, p62 and modified Bielschowsky silver, and the midbrain stained only for modified Bielschowsky silver. Accuracy of interrater reliability was determined by 10 raters in 24 FTLD-tau cases (Pick disease = 4, corticobasal degeneration = 9, progressive supranuclear palsy = 5, globular glial tauopathy = 6) including 4 with a mutation in MAPT collected with consent by Sydney Brain Bank. All brain regions and stains assessed proved informative for accurate pathological subtyping, and many neuropathological features were identified as common across the FTLD-tau subtypes. By identifying subtype-specific neuropathological features in the sections selected, 10 independent observers assigned the cases to a FTLD-tau subtype with almost perfect agreement between raters, emphasizing the requirement for the assessment of subtype-specific features for the accurate subtyping of FTLD-tau. This study consolidates current consensus diagnostic criteria for classifying FTLD-tau subtypes with an efficient, simple and accurate approach that can be implemented in future clinicopathological studies.

scholarly journals Proteomic Analysis Unveils Expressional Changes in Cytoskeleton- and Synaptic Plasticity-Associated Proteins in Rat Brain Six Months after Withdrawal from Morphine

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 683
Author(s):  
Zdenka Drastichova ◽  
Lucie Hejnova ◽  
Radka Moravcova ◽  
Jiri Novotny
Keyword(s):  
Synaptic Plasticity ◽  
Proteomic Analysis ◽  
Molecular Mechanisms ◽  
Brain Regions ◽  
Morphine Withdrawal ◽  
Synaptic Proteins ◽  
Label Free ◽  
Presynaptic Nerve Terminal ◽  
Cytoskeleton Organization ◽  
Associated Proteins

Drug withdrawal is associated with abstinence symptoms including deficits in cognitive functions that may persist even after prolonged discontinuation of drug intake. Cognitive deficits are, at least partially, caused by alterations in synaptic plasticity but the precise molecular mechanisms have not yet been fully identified. In the present study, changes in proteomic and phosphoproteomic profiles of selected brain regions (cortex, hippocampus, striatum, and cerebellum) from rats abstaining for six months after cessation of chronic treatment with morphine were determined by label-free quantitative (LFQ) proteomic analysis. Interestingly, prolonged morphine withdrawal was found to be associated especially with alterations in protein phosphorylation and to a lesser extent in protein expression. Gene ontology (GO) term analysis revealed enrichment in biological processes related to synaptic plasticity, cytoskeleton organization, and GTPase activity. More specifically, significant changes were observed in proteins localized in synaptic vesicles (e.g., synapsin-1, SV2a, Rab3a), in the active zone of the presynaptic nerve terminal (e.g., Bassoon, Piccolo, Rims1), and in the postsynaptic density (e.g., cadherin 13, catenins, Arhgap35, Shank3, Arhgef7). Other differentially phosphorylated proteins were associated with microtubule dynamics (microtubule-associated proteins, Tppp, collapsin response mediator proteins) and the actin–spectrin network (e.g., spectrins, adducins, band 4.1-like protein 1). Taken together, a six-month morphine withdrawal was manifested by significant alterations in the phosphorylation of synaptic proteins. The altered phosphorylation patterns modulating the function of synaptic proteins may contribute to long-term neuroadaptations induced by drug use and withdrawal.

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