scholarly journals A human huntingtin SNP alters post-translational modification and pathogenic proteolysis of the protein causing Huntington disease

2017 ◽  
Author(s):  
DDO Martin ◽  
C Kay ◽  
JA Collins ◽  
YT Nguyen ◽  
RA Slama ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Protein Function ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Genetic Modifier ◽  
Human Cells ◽  
Missense Mutations ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Normal Functions

AbstractPost-translational modifications (PTMs) are key modulators of protein function. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene. A spectrum of PTMs have been shown to modify the normal functions of HTT, including proteolysis, phosphorylation and lipidation, but the full contribution of these PTMs to the molecular pathogenesis of HD remains unclear. In this study, we examine all commonly occurring missense mutations in HTT to identify potential human modifiers of HTT PTMs relevant to HD biology. We reveal a SNP that modifies post-translational myristoylation of HTT, resulting in downstream alterations to toxic HTT proteolysis in human cells. This is the first SNP shown to functionally modify a PTM in HD and the first validated genetic modifier of post-translational myristoylation. This SNP is a high-priority candidate modifier of HD phenotypes and may illuminate HD biology in human studies.

scholarly journals Post translational modifications of milk proteins in geographically diverse goat breeds

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
P. K. Rout ◽  
M. Verma
Keyword(s):  
Protein Function ◽  
Whey Proteins ◽  
Milk Proteins ◽  
Goat Milk ◽  
Peptide Sequence ◽  
Cow Milk ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Functional Roles ◽  
Dpp Iv

AbstractGoat milk is a source of nutrition in difficult areas and has lesser allerginicity than cow milk. It is leading in the area for nutraceutical formulation and drug development using goat mammary gland as a bioreactor. Post translational modifications of a protein regulate protein function, biological activity, stabilization and interactions. The protein variants of goat milk from 10 breeds were studied for the post translational modifications by combining highly sensitive 2DE and Q-Exactive LC-MS/MS. Here we observed high levels of post translational modifications in 201 peptides of 120 goat milk proteins. The phosphosites observed for CSN2, CSN1S1, CSN1S2, CSN3 were 11P, 13P, 17P and 6P, respectively in 105 casein phosphopeptides. Whey proteins BLG and LALBA showed 19 and 4 phosphosites respectively. Post translational modification was observed in 45 low abundant non-casein milk proteins mainly associated with signal transduction, immune system, developmental biology and metabolism pathways. Pasp is reported for the first time in 47 sites. The rare conserved peptide sequence of (SSSEE) was observed in αS1 and αS2 casein. The functional roles of identified phosphopeptides included anti-microbial, DPP-IV inhibitory, anti-inflammatory and ACE inhibitory. This is first report from tropics, investigating post translational modifications in casein and non-casein goat milk proteins and studies their interactions.

scholarly journals iProteinDB: an integrative database of Drosophila post-translational modifications

2018 ◽  
Author(s):  
Yanhui Hu ◽  
Richelle Sopko ◽  
Verena Chung ◽  
Romain A. Studer ◽  
Sean D. Landry ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Large Scale ◽  
Model Organisms ◽  
General Strategy ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Functional Sites ◽  
Evolutionarily Conserved ◽  
And Function

AbstractPost-translational modification (PTM) serves as a regulatory mechanism for protein function, influencing stability, protein interactions, activity and localization, and is critical in many signaling pathways. The best characterized PTM is phosphorylation, whereby a phosphate is added to an acceptor residue, commonly serine, threonine and tyrosine. As proteins are often phosphorylated at multiple sites, identifying those sites that are important for function is a challenging problem. Considering that many phosphorylation sites may be non-functional, prioritizing evolutionarily conserved phosphosites provides a general strategy to identify the putative functional sites with regards to regulation and function. To facilitate the identification of conserved phosphosites, we generated a large-scale phosphoproteomics dataset from Drosophila embryos collected from six closely-related species. We built iProteinDB (https://www.flyrnai.org/tools/iproteindb/), a resource integrating these data with other high-throughput PTM datasets, including vertebrates, and manually curated information for Drosophila. At iProteinDB, scientists can view the PTM landscape for any Drosophila protein and identify predicted functional phosphosites based on a comparative analysis of data from closely-related Drosophila species. Further, iProteinDB enables comparison of PTM data from Drosophila to that of orthologous proteins from other model organisms, including human, mouse, rat, Xenopus laevis, Danio rerio, and Caenorhabditis elegans.

scholarly journals Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity

2014 ◽  
Vol 462 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Kristen E. Funk ◽  
Stefani N. Thomas ◽  
Kelsey N. Schafer ◽  
Grace L. Cooper ◽  
Zhongping Liao ◽  
...  
Keyword(s):  
Human Brain ◽  
Tau Protein ◽  
Protein Function ◽  
Lysine Methylation ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Aggregation Propensity ◽  
Normal Human ◽  
Tau Aggregation

Diverse post-translational modifications regulate tau protein function and misfolding. In the present study we identified lysine methylation as a tau post-translational modification in normal human brain, and found it depressed tau aggregation propensity when modelled in vitro.

scholarly journals Library preparation and MiSeq sequencing for the genotyping-by-sequencing of the Huntington disease HTT exon one trinucleotide repeat and the quantification of somatic mosaicism

2020 ◽  
Author(s):  
Marc Ciosi ◽  
Sarah A. Cumming ◽  
Asma M. Alshammari ◽  
Efthymia Symeonidi ◽  
Pawel Herzyk ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Fragment Size ◽  
Somatic Mosaicism ◽  
Genotyping By Sequencing ◽  
Amplicon Sequencing ◽  
Cag Repeat ◽  
Miseq Sequencing ◽  
Flanking Sequence

Abstract Huntington disease \(HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the _HTT_ gene. Affected individuals inherit more than 40 repeats and the CAG repeat is genetically unstable in both the germline and soma. Molecular diagnosis and genotyping of the CAG repeat is traditionally performed by estimation of PCR fragment size. However, this approach is complicated by the presence of an adjacent polymorphic CCG repeat and provides no information on the presence of variant repeats, flanking sequence variants or on the degree of somatic mosaicism. To overcome these limitations, we have developed an amplicon-sequencing protocol that allows the sequencing of hundreds of samples in a single MiSeq run. The composition of the _HTT_ exon one trinucleotide repeat locus can be determined from the MiSeq sequencing reads generated. With sufficient sequencing depth, such MiSeq data can also be used to quantify the degree of somatic mosaicism of the _HTT_ CAG repeat in the tissue analysed.

scholarly journals Site-specific phosphorylation and caspase cleavage of GFAP are new markers of Alexander disease severity

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rachel A Battaglia ◽  
Adriana S Beltran ◽  
Samed Delic ◽  
Raluca Dumitru ◽  
Jasmine A Robinson ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Neurodegenerative Disorder ◽  
Induced Pluripotent Stem Cell ◽  
Alexander Disease ◽  
Missense Mutations ◽  
Post Translational Modifications ◽  
Caspase Cleavage ◽  
Caspase 6 ◽  
Induced Pluripotent

Alexander disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD.

scholarly journals Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

2021 ◽  
Vol 11 ◽  
Author(s):  
Carolina Alquezar ◽  
Shruti Arya ◽  
Aimee W. Kao
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Protein Localization ◽  
Critical Role ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Tau Function ◽  
Potential Impact ◽  
Important Position

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies.

scholarly journals Single-Step Scalable-Throughput Molecular Screening for Huntington Disease

2008 ◽  
Vol 54 (6) ◽  
pp. 964-972 ◽  
Author(s):  
Clara R L Teo ◽  
Wen Wang ◽  
Hai Yang Law ◽  
Caroline G Lee ◽  
Samuel S Chong
Keyword(s):  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
False Positive Rate ◽  
Screening Method ◽  
Melting Curve ◽  
Single Step ◽  
Cag Repeat ◽  
Clinical Samples ◽  
Melting Curve Analysis

Abstract Background: Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by an unstable expansion of the CAG trinucleotide repeat in exon 1 of the HTT (huntingtin) gene and typically has an adult onset. Molecular diagnosis and screening for HD currently involve separate amplification and detection steps. Methods: We evaluated a novel, rapid microplate-based screening method for HD that combines the amplification and detection procedures in a single-step, closed-tube format. We carried out both the PCR for the HTT CAG-repeat region and the subsequent automated melting-curve analysis of the amplicon in the same wells on the plate. To establish cutoff melting temperatures (Tms) for each allelic class, we used a panel of reference DNA samples of known CAG-repeat sizes that represent a range of HTT alleles [normal (≤26 repeats), intermediate (27–35 repeats), reduced penetrance expanded (36–39 repeats), and fully penetrant expanded (≥40 repeats)]. We also measured well-to-well variation in Tm across the thermal block and validated cutoff Tms with DNA samples from 5 different populations. We also conducted a blinded validation analysis of clinical samples from an additional 40 HD-affected and 30 unaffected individuals. Results: We observed a strong correlation between CAG-repeat size and amplicon Tm among the reference DNA samples. Use of the Tm cutoffs we established revealed that 5 samples from unaffected individuals had been misclassified as affected (1.1% false-positive rate). All samples from HD-affected and unaffected individuals were correctly identified in the blinded analysis. Conclusions: This simple and scalable homogeneous assay may serve as a convenient, rapid, and accurate screen to detect the presence of pathologic expanded HD alleles in symptomatic patients.

scholarly journals Nonisotopic method for accurate detection of (CAG)n repeats causing Huntington disease

1996 ◽  
Vol 42 (10) ◽  
pp. 1601-1603 ◽  
Author(s):  
M Muglia ◽  
O Leone ◽  
G Annesi ◽  
A L Gabriele ◽  
E Imbrogno ◽  
...  
Keyword(s):  
Silver Nitrate ◽  
Molecular Diagnosis ◽  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
The Novel ◽  
Direct Visualization ◽  
Pcr Products ◽  
Radioactive Background ◽  
Presymptomatic Diagnosis

Abstract Huntington disease (HD) is a neurodegenerative disorder caused by an expanded trinucleotide repeat (CAG)n located at the 5' end of the novel IT15 gene. Discovery of this expansion allows the molecular diagnosis of HD by measuring repeat length. We applied a simple nonisotopic method to detect (CAG)n repeats, avoiding both radioactive and Southern transfer analysis. The assay is based on direct visualization of electrophoresed PCR products, after silver nitrate gel staining. Its accurate sizing of HD alleles allows presymptomatic diagnosis of at-risk persons. By avoiding isotopic manipulations, the method is safe and accurate, with no radioactive background bands. Furthermore, because it permits direct allele visualization after gel staining, the method is simple and rapid, allowing allele sizing within hours rather than days.

Prediction of lysine post-translational modifications using bioinformatic tools

2012 ◽  
Vol 52 ◽  
pp. 165-177 ◽  
Author(s):  
Daniel Schwartz
Keyword(s):  
Protein Function ◽  
Data Sets ◽  
Valuable Insight ◽  
Post Translational Modification ◽  
Computational Tools ◽  
Post Translational Modifications ◽  
Bioinformatic Tools ◽  
Lysine Modification ◽  
Testing Data ◽  
Experimental Biologist

Our understanding of the importance of lysine post-translational modifications in mediating protein function has led to a significant improvement in the experimental tools aimed at characterizing their existence. Nevertheless, it remains likely that at present we have only experimentally detected a small fraction of all lysine modification sites across the commonly studied proteomes. As a result, online computational tools aimed at predicting lysine modification sites have the potential to provide valuable insight to researchers developing hypotheses regarding these modifications. This chapter discusses the metrics and procedures used to assess predictive tools and surveys 11 online computational tools aimed at the prediction of the four most widely studied lysine post-translational modifications (acetylation, methylation, SUMOylation and ubiquitination). Analyses using unbiased testing data sets suggest that nine of the 11 lysine post-translational modification tools perform no better than random, or have false-positive rates which make them unusable by the experimental biologist, despite self-reported sensitivity and specificity values to the contrary. The implications of these findings for those using and creating lysine post-translational modification software are discussed.

Huntington Disease: Clinical, Genetic, and Social Aspects

1998 ◽  
Vol 11 (2) ◽  
pp. 61-70 ◽  
Author(s):  
Martha A. Nance
Keyword(s):  
Huntington Disease ◽  
Collaborative Research ◽  
Autosomal Dominant ◽  
Trinucleotide Repeat ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Social Aspects ◽  
Clinical Genetic ◽  
Behavioral Disturbances ◽  
Neurogenetic Disorders

Huntington disease (HD) is a fascinating neurodegenerative disorder whose features straddle the boundaries of psychiatry, neurology, and genetics. The clinical symptoms of HD consist of a triad of motor, cognitive, and psychiatric/behavioral disturbances. In 1993, the HD Collaborative Research Group identified the gene and the mutation responsible for HD. HD was one of the first neurodegenerative disorders discovered to be caused by a novel mutational mechanism known as trinucleotide repeat expansion. Since then, HD has been the model for autosomal dominant neurogenetic disorders. The clinical, pathological, and genetic aspects of the disease are reviewed and some of the questions that remain to be answered by researchers of the 21st century are outlined.

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