Uncovering Neurodegenerative Protein Modifications via Proteomic Profiling

Gallart‐Palau, Xavier; Serra, Aida; Sze, Siu Kwan

doi:10.1016/bs.irn.2015.06.002

Cited by 32 publications

(44 citation statements)

References 154 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Proteomic of pathological progression from hypoxiaischemia brain injury to clinical dementia revealed the dysregulation of energy metabolism, mitochondrial dysfunction, neuro-inflammation, synaptic failure, etc. [24][25][26]50]. Further, the activity of α-ketoglutarate dehydrogenase appears to be inhibited in the cerebral cortex of AD patients, and there are substantial evidences indicating that the function of the Krebs cycle is impaired in AD brains [51,52].…”

Section: Insights From Hypoxia/ischemia-induced Neuropathymentioning

confidence: 99%

“…Following synapses loss, the remaining synapses alter their shape. According to recent literature [26], synaptic immunoglobulins were perturbed proteins in VaD temporal cortices, while SNAP25 was substantially upregulated. Further, deamidation studies revealed that the protein synapsin 1 displayed significant accumulation of deamidated asparagine and glutamine residues when compared with age-matched control [30].…”

Section: Deamidation Of Ion Channel and Other Proteins In Dementiamentioning

confidence: 99%

“…Proteomic technique enables the comprehensive analysis of the protein and its work flow involves the identification of proteins following their separation, digestion by trypsin, determination of the molecular weight of the resulting peptides, and database searching to make the identification and quantification of the proteins as well as the characterization of the DPMs. In addition to label-free proteomic methods, isobaric tags for relative and absolute quantitation (iTRAQ) and tandem mass tag (TMT) protein labeling are widely accepted approaches for quantitative profiling of cell lines and clinical brain tissue samples [24][25][26]. Proteomics has also been used for the accurate identification of protein modifications [26][27][28][29][30][31].…”

Section: Proteomics Studies Of Dementia and Admentioning

confidence: 99%

“…Hence, an accurate identification of DMPs and modification sites is important to understand the role of DPMs in human diseases. A comprehensive investigation including method development for accurate identification of DPMs has been performed for biomedical research [24,26,27,30,31,34,35]. Loss of synapses is one of the most significant contributors to the cognitive impairment manifest in VaD and other neurodegenerative diseases.…”

Section: Deamidation Of Ion Channel and Other Proteins In Dementiamentioning

confidence: 99%

“…The conditions such as hypoxia/ischemia have been linked to the pathogenesis of AD [46]. Unbiased proteomic analysis of hypoxia-ischemia pathology in numerous disease models and clinical setting including neuronal cell lines [47], a rat model of ischemic middle cerebral artery occlusion [48], a mouse model of cardiovascular disease [49], blood or tissues samples from patients with dementia [24,26,30] has provided novel insight into molecular pathology of hypoxia-ischemic injury and confirmed that hypoxia induced mitochondrial dysfunction and oxidative stress, induced epigenetic changes, and dysregulated proteostasis. Thus, oxygen availability is a crucial regulator of cellular metabolism and homeostasis.…”

Section: Insights From Hypoxia/ischemia-induced Neuropathymentioning

confidence: 99%

See 4 more Smart Citations

Proteomic Study of Degenerative Protein Modifications in the Molecular Pathology of Neurodegeneration and Dementia

Adav¹,

Sze²

2016

Update on Dementia

Self Cite

View full text Add to dashboard Cite

Dementia is a major public health burden, and the World Health Organization has identified this disorder as a major public health priority. There are limited treatment options due to poor understanding of key mechanism of dementia pathogenesis. Dementia has been regarded as a proteinopathy in which alterations of brain protein structure and function are the key features of the disorder. Proteinopathy can be triggered by degenerative protein modifications (DPMs), misfolding, aggregation, and deposition of the malformed proteins. Despite the clinical significance of alteration in protein abundances, DPMs, protein misfolding, and aggregation, the molecular mechanism that promotes these changes remains inadequately understood, mostly due to technical challenges. Proteomic is a powerful, sensitive, and advanced tool to study the progressive brain tissue damage that critically dysregulates key enzymes, accumulates modified proteins, and causes protein misfolding and aggregation, resulting in cognitive decline and dementia. The proteomic profiling of protein abundances and correlating DPMs with protein misfolding and aggregation have potential to elucidate underlying molecular mechanism of the disease. This chapter summarizes the recent proteomic developments for studying brain proteome, DPMs, and protein aggregation mechanism that may lead to dementia. We attempted to correlate DPMs and its impact on protein aggregation and deposition in brain tissues.

show abstract

Section: Insights From Hypoxia/ischemia-induced Neuropathymentioning

confidence: 99%

Section: Deamidation Of Ion Channel and Other Proteins In Dementiamentioning

confidence: 99%

Section: Proteomics Studies Of Dementia and Admentioning

confidence: 99%

Section: Deamidation Of Ion Channel and Other Proteins In Dementiamentioning

confidence: 99%

Section: Insights From Hypoxia/ischemia-induced Neuropathymentioning

confidence: 99%

See 3 more Smart Citations

Proteomic Study of Degenerative Protein Modifications in the Molecular Pathology of Neurodegeneration and Dementia

Adav¹,

Sze²

2016

Update on Dementia

Self Cite

View full text Add to dashboard Cite

show abstract

Association of Plasma Metabolomic Biomarkers With Persistent Tinnitus

Zeleznik

Welling

Stanković

et al. 2023

JAMA Otolaryngol Head Neck Surg

View full text Add to dashboard Cite

ImportancePersistent tinnitus is common, disabling, and difficult to treat.ObjectiveTo evaluate the association between circulating metabolites and persistent tinnitus.Design, Setting, and ParticipantsThis was a population-based case-control study of 6477 women who were participants in the Nurses’ Health Study (NHS) and NHS II with metabolomic profiles and tinnitus data. Information on tinnitus onset and frequency was collected on biennial questionnaires (2009-2017). For cases, metabolomic profiles were measured (2015-2021) in blood samples collected after the date of the participant’s first report of persistent tinnitus (NHS, 1989-1999 and 2010-2012; NHS II, 1996-1999). Data analyses were performed from January 24, 2022, to January 14, 2023.ExposuresIn total, 466 plasma metabolites from 488 cases of persistent tinnitus and 5989 controls were profiled using 3 complementary liquid chromatography tandem mass spectrometry approaches.Main Outcomes and MeasuresLogistic regression was used to estimate odds ratios (ORs) of persistent tinnitus (per 1 SD increase in metabolite values) and 95% CIs for each individual metabolite. Metabolite set enrichment analysis was used to identify metabolite classes enriched for associations with tinnitus.ResultsOf the 6477 study participants (mean [SD] age, 52 [9] years; 6477 [100%] female; 6121 [95%] White individuals) who were registered nurses, 488 reported experiencing daily persistent (≥5 minutes) tinnitus. Compared with participants with no tinnitus (5989 controls), those with persistent tinnitus were slightly older (53.0 vs 51.8 years) and more likely to be postmenopausal, using oral postmenopausal hormone therapy, and have type 2 diabetes, hypertension, and/or hearing loss at baseline. Compared with controls, homocitrulline (OR, 1.32; (95% CI, 1.16-1.50); C38:6 phosphatidylethanolamine (PE; OR, 1.24; 95% CIs, 1.12-1.38), C52:6 triglyceride (TAG; OR, 1.22; 95% CIs, 1.10-1.36), C36:4 PE (OR, 1.22; 95% CIs, 1.10-1.35), C40:6 PE (OR, 1.22; 95% CIs, 1.09-1.35), and C56:7 TAG (OR, 1.21; 95% CIs, 1.09-1.34) were positively associated, whereas α-keto-β-methylvalerate (OR, 0.68; 95% CIs, 0.56-0.82) and levulinate (OR, 0.60; 95% CIs, 0.46-0.79) were inversely associated with persistent tinnitus. Among metabolite classes, TAGs (normalized enrichment score [NES], 2.68), PEs (NES, 2.48), and diglycerides (NES, 1.65) were positively associated, whereas phosphatidylcholine plasmalogens (NES, −1.91), lysophosphatidylcholines (NES, −2.23), and cholesteryl esters (NES,−2.31) were inversely associated with persistent tinnitus.Conclusions and RelevanceThis population-based case-control study of metabolomic profiles and tinnitus identified novel plasma metabolites and metabolite classes that were significantly associated with persistent tinnitus, suggesting that metabolomic studies may help improve understanding of tinnitus pathophysiology and identify therapeutic targets for this challenging disorder.

show abstract

Identification of Novel Site-Specific Alterations in the Modification Level of Myelin Basic Protein Isolated from Mouse Brain at Different Ages Using Capillary Electrophoresis-Mass Spectrometry

2017

View full text Add to dashboard Cite

Myelin basic protein (MBP) is a multifunctional protein involved in maintaining the stability and integrity of the myelin sheath by a variety of interactions with membranes and other proteins. MBP is subjected to extensive posttranslational modifications (PTMs) that are known to be crucial for the regulation of these interactions. Here, we report capillary electrophoresis-mass spectrometric (CE-MS) analysis for the separation and identification of MBP peptides that incorporate the same PTM at different sites, creating multiple localization variants, and the ability to analyze challenging modifications such as asparagine and glutamine deamidation, isomerization, and arginine citrullination. Moreover, we observed site-specific alterations in the modification level of MBP purified from brain of mice of different age. In total, we identified 40 modifications at 33 different sites, which include both previously reported and seven novel modifications. The identified modifications include Nα-terminal acetylation, mono- and dimethylation, phosphorylation, oxidation, deamidation, and citrullination. Notably, some new sites of arginine methylation overlap with the sites of citrullination. Our results highlight the need for sensitive and efficient techniques for a comprehensive analysis of PTMs.

show abstract

Uncovering Neurodegenerative Protein Modifications via Proteomic Profiling

Cited by 32 publications

References 154 publications

Proteomic Study of Degenerative Protein Modifications in the Molecular Pathology of Neurodegeneration and Dementia

Proteomic Study of Degenerative Protein Modifications in the Molecular Pathology of Neurodegeneration and Dementia

Association of Plasma Metabolomic Biomarkers With Persistent Tinnitus

Identification of Novel Site-Specific Alterations in the Modification Level of Myelin Basic Protein Isolated from Mouse Brain at Different Ages Using Capillary Electrophoresis-Mass Spectrometry

Contact Info

Product

Resources

About