Mapping Post-Translational Modifications in Brain Regions in Alzheimer's Disease Using Proteomics Data Mining

Deolankar, Sayali Chandrashekhar; Patil, Arun H.; Rex, Devasahayam Arokia Balaya; Subba, Pratigya; Mahadevan, Anita; Prasad, T. S. Keshava

doi:10.1089/omi.2021.0054

Cited by 8 publications

(6 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 C and 3D) suggesting post-transcriptional and/or post-translational modifications such as a possibility of accelerated LRP10 protein degradation with compensatory up-regulation of transcriptional machinery. The discordance or decoupling in mRNA and protein expression of the same genes has been reported in studies with human aging [ 67 ] and neurodegenerative disorders such as tauopathy [ 68 ] and AD [ 69 ] with proposed mechanisms such as changes in expression profiles of RNA binding proteins and microRNAs [ 67 ], as well as post-translational modifications with changes in protein folding, degradation and/or half-lives [ 69 – 72 ]. Based on our findings, we are currently studying whether half-lives of lrp10 mRNA and LRP10 protein are specifically altered in female APOE4 +/- AD brain cells when compared to other counterparts.…”

Section: Discussionmentioning

confidence: 99%

Sex specific molecular networks and key drivers of Alzheimer’s disease

Guo

Cao

Hou

et al. 2023

Mol Neurodegeneration

View full text Add to dashboard Cite

Background Alzheimer’s disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD. Methods We integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models. Results Gene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development. LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34. Conclusions These findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Sex specific molecular networks and key drivers of Alzheimer’s disease

Guo

Cao

Hou

et al. 2023

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…Another study utilized the PRIDE database to study post-translational modifications in AD patients. They report 103 proteins with post translational modifications that are uniquely expressed between brain region with no tangles, intermediate tangles, and severe tangles [ 95 ]. The bioinformatics analysis suggested the association of these proteins in AD progression through platelet activation, and they were found to be enriched for the tricarboxylic acid cycle (Kreb's Cycle), respiratory electron cycle, and detoxification of reactive oxygen species [ 95 ].…”

Section: Omics Spectrum-based Data Mining In Translational Neurosciencementioning

confidence: 99%

Integrative multi-omics and systems bioinformatics in translational neuroscience: A data mining perspective

O’Connor

Lim

et al. 2023

Journal of Pharmaceutical Analysis

View full text Add to dashboard Cite

“…Significant efforts and resources have been utilized in the identification of malaria parasite proteins toward developing better diagnostics and vaccines. The emphasis has been on identifying protein targets and characterizing various cytoplasmic, cell surface, and secreted proteins. , Mass spectrometry-based quantitative phosphoproteomic analysis has been used to study specific phosphorylation-based molecular targets and associated signaling in apicomplexan parasites. − While several investigations involved prior enrichment of specific post-translational modifications (PTMs), a combination of advanced bioinformatics strategies can be adopted to fetch several PTMs from the large-scale proteomic data sets without a priori enrichment for those PTMs. , Although a set of protocols used for such a multi-PTM analysis appears to be simple, it needs sophisticated computational infrastructure and takes more time when compared to routine proteomic analysis …”

Section: Introductionmentioning

confidence: 99%

“…These MS/MS data may contain different PTMs or novel peptides not represented in the protein database. The unassigned spectral data can be mined for fetching multiple post-translational modifications (multi-PTMs), including phosphorylation, glutarylation, succinylation, and acetylation, among others. − The unassigned MS/MS data can also be subjected to proteogenomic analysis to identify novel peptides, which can help define novel protein-coding regions. Several studies from across the world, including our group, have shown that proteogenomics helps refine genome annotation and identify taxonomically diverse reference proteomes. − In this study, we reported the discovery of 43 unique protein-coding genes from P.…”

Section: Introductionmentioning

confidence: 99%

“…6−8 While several investigations involved prior enrichment of specific post-translational modifications (PTMs), a combination of advanced bioinformatics strategies can be adopted to fetch several PTMs from the large-scale proteomic data sets without a priori enrichment for those PTMs. 9,10 Although a set of protocols used for such a multi-PTM analysis appears to be simple, it needs sophisticated computational infrastructure and takes more time when compared to routine proteomic analysis. 11 PTMs are the result of either covalent linking of functional groups to amino acid residues or proteolytic cleavage.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dissecting Plasmodium yoelii Pathobiology: Proteomic Approaches for Decoding Novel Translational and Post-Translational Modifications

et al. 2022

Self Cite

View full text Add to dashboard Cite

Malaria is a vector-borne disease. It is caused by Plasmodium parasites. Plasmodium yoelii is a rodent model parasite, primarily used for studying parasite development in liver cells and vectors. To better understand parasite biology, we carried out a high-throughput-based proteomic analysis of P. yoelii. From the same mass spectrometry (MS)/MS data set, we also captured several post-translational modified peptides by following a bioinformatics analysis without any prior enrichment. Further, we carried out a proteogenomic analysis, which resulted in improvements to some of the existing gene models along with the identification of several novel genes. Analysis of proteome and post-translational modifications (PTMs) together resulted in the identification of 3124 proteins. The identified PTMs were found to be enriched in mitochondrial metabolic pathways. Subsequent bioinformatics analysis provided an insight into proteins associated with metabolic regulatory mechanisms. Among these, the tricarboxylic acid (TCA) cycle and the isoprenoid synthesis pathway are found to be essential for parasite survival and drug resistance. The proteogenomic analysis discovered 43 novel protein-coding genes. The availability of an in-depth proteomic landscape of a malaria pathogen model will likely facilitate further molecular-level investigations on pre-erythrocytic stages of malaria.

show abstract

Mapping Post-Translational Modifications in Brain Regions in Alzheimer's Disease Using Proteomics Data Mining

Cited by 8 publications

References 65 publications

Sex specific molecular networks and key drivers of Alzheimer’s disease

Sex specific molecular networks and key drivers of Alzheimer’s disease

Integrative multi-omics and systems bioinformatics in translational neuroscience: A data mining perspective

Dissecting Plasmodium yoelii Pathobiology: Proteomic Approaches for Decoding Novel Translational and Post-Translational Modifications

Contact Info

Product

Resources

About