Hypoxia-Induced Degenerative Protein Modifications Associated with Aging and Age-Associated Disorders

Abstract

Aging is an inevitable time-dependent decline of various physiological functions that finally leads to death. Progressive protein damage and aggregation have been proposed as the root cause of imbalance in regulatory processes and risk factors for aging and neurodegenerative diseases. Oxygen is a modulator of aging. The oxygen-deprived conditions (hypoxia) leads to oxidative stress, cellular damage and protein modifications. Despite unambiguous evidence of the critical role of spontaneous non-enzymatic Degenerative Protein Modifications (DPMs) such as oxidation, glycation, carbonylation, carbamylation, and deamidation, that impart deleterious structural and functional protein alterations during aging and age-associated disorders, the mechanism that mediates these modifications is poorly understood. This review summarizes up-to-date information and recent developments that correlate DPMs, aging, hypoxia, and age-associated neurodegenerative diseases. Despite numerous advances in the study of the molecular hallmark of aging, hypoxia, and degenerative protein modifications during aging and age-associated pathologies, a major challenge remains there to dissect the relative contribution of different DPMs in aging (either natural or hypoxia-induced) and age-associated neurodegeneration.

Keywords: aging; dementia; hypoxia; neurodegenerative disease; protein aggregation; proteomics; proteostasis.

Figure 1.

Schematics of nine hallmark of aging (adopted from López-Otín et al.[6]). The figure specifies the nine hallmarks of aging such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.

Figure 2.

Advanced novel proteomic approaches to elucidate degenerative protein modifications (DPMs) and post-translational modifications (PTMs) of protein in aging, hypoxia and neurodegenerative diseases or other biological samples. (VaD: vascular dementia, CSF: cerebrospinal fluid, CI: cerebral ischemia, AD: Alzheimer disease, PD: Parkinson disease)

Figure 3.

Possible routes of AGE formation (Adopted from Kikuchi et al[208]). AGEs get generated through decomposition of Amadori products, from glycolysis intermediates like glyceraldehyde, a Schiff base fragmentation product such as glycolaldehyde, fragmentation of Amadori products including methylglyoxal and 3-deoxyglucosone, and the autoxidation of glucose to glyoxal. (GO imidazolone, glyoxal imidazolone; MGO imidazolone, methylglyoxal imidazolone).

Figure 4.

Separation of Asn and Gln deamidation peptides from trypsin-digested human brain tissue using LERLIC-MS/MS. (Adopted from Serra et al.[233]) A) Extracted ion chromatograms of peptide N#GFDQCDYGWLSDASVR showing separated triad of Asn deamidated peptides B) Extracted ion chromatograms of VDKGVVPLAGTN#GETTTQGLDGLSER peptide showing separation of carbon-13 peak of nondeamidated peptide (Asn_C13), Asp (aspartyl isomer) and isoaspartyl isomer (isoAsn), C) Extracted ion chromatograms of GVVPLAGTNGETTTQGLDGLSER nondeamidated peptide, D) Extracted ion chromatograms of two deamidated proteoforms with asn and Gln deamidated residues in peptide GVVPLAGTN#GETTTQGLDGLSER and GVVPLAGTNGETTTQ#GLDGLSER where Gln-Asn_c13 is a carbon-13 peak of the nondeamidated peptide; α-Glu is α-glutamyl isomer; Asp is Asp aspartyl isomer; γ-Glu is γ-glutamyl isomer; and isoAsp reamin isoaspartyl isomer. #indicates site of modification.