Racemization hypothesis of neurodegeneration (RHND)

Dyakin, Victor V.; Lajtha, Ábel; Dyakina‐Fagnano, Nika Victorovna

doi:10.1002/alz.047697

Cited by 3 publications

(7 citation statements)

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“…Another part of PTMs Sp is known to disrupt the natural course of molecular events, often leading to pathogenic misfolding, malfunction, and aggregation of proteins. One of the most studied forms of pathogenic reactions is racemization [ 69 , 70 ]. As an unavoidable consequence of pathogenic PTMs, we can expect that even small (limited only to one or two AAs) racemization can trigger the deviation from the NS.…”

Section: Biological Language Of Protein Conformationmentioning

confidence: 99%

Arrow of Time, Entropy, and Protein Folding: Holistic View on Biochirality

Dyakin

Uversky

2022

IJMS

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Chirality is a universal phenomenon, embracing the space–time domains of non-organic and organic nature. The biological time arrow, evident in the aging of proteins and organisms, should be linked to the prevalent biomolecular chirality. This hypothesis drives our exploration of protein aging, in relation to the biological aging of an organism. Recent advances in the chirality discrimination methods and theoretical considerations of the non-equilibrium thermodynamics clarify the fundamental issues, concerning the biphasic, alternative, and stepwise changes in the conformational entropy associated with protein folding. Living cells represent open, non-equilibrium, self-organizing, and dissipative systems. The non-equilibrium thermodynamics of cell biology are determined by utilizing the energy stored, transferred, and released, via adenosine triphosphate (ATP). At the protein level, the synthesis of a homochiral polypeptide chain of L-amino acids (L-AAs) represents the first state in the evolution of the dynamic non-equilibrium state of the system. At the next step the non-equilibrium state of a protein-centric system is supported and amended by a broad set of posttranslational modifications (PTMs). The enzymatic phosphorylation, being the most abundant and ATP-driven form of PTMs, illustrates the principal significance of the energy-coupling, in maintaining and reshaping the system. However, the physiological functions of phosphorylation are under the permanent risk of being compromised by spontaneous racemization. Therefore, the major distinct steps in protein-centric aging include the biosynthesis of a polypeptide chain, protein folding assisted by the system of PTMs, and age-dependent spontaneous protein racemization and degradation. To the best of our knowledge, we are the first to pay attention to the biphasic, alternative, and stepwise changes in the conformational entropy of protein folding. The broader view on protein folding, including the impact of spontaneous racemization, will help in the goal-oriented experimental design in the field of chiral proteomics.

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Section: Biological Language Of Protein Conformationmentioning

confidence: 99%

Arrow of Time, Entropy, and Protein Folding: Holistic View on Biochirality

Dyakin

Uversky

2022

IJMS

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“…The accumulation of unfolded/misfolded proteins activate a series of cell-specific stress responses, including unfolded protein response (UPR) [78,79]. In neuronal cells, the aggregates of b Proteins kinetically trapped in the local E min have a prolonged lifetime which increases the probability of the spontaneous PTMs [1,2,13,14] Fragments are adopted with the alterations from [71,72,73].…”

Section: Afterwordmentioning

confidence: 99%

“…The prevalent molecular chirality plays a causal role in neuronal polarity and motility, which in turn, are the cellular determinant of the brain bilaterality and the asymmetry of perceptual, cognitive, and behavioral functions [1,2,3]. Generally speaking, brain-body mediated interaction of the internal bio-molecular chirality with the external environment's chiral factor occurs due to the hierarchical chain of chirality transfer [1] associated with the hierarchical organization of living systems [4].…”

Section: Introductionmentioning

confidence: 99%

“…[19] share many common chemical, metabolic and thermodynamic attributes. Spontaneous racemization and accumulation of advanced glycation end-products (AGPs) have been most intensively studied concerning protein aging, aggregation, and dysfunctions in the fields of neuroscience [1][2][3] and forensic applications [15]. In our review, we are considering the contribution of spontaneous racemization [13,23] and non-enzymatic glycosylation [24 -26] to protein aging.…”

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confidence: 99%

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Spontaneous Determinants of Protein Aging Mini Review

Dyakin¹,

Uversky²

2021

Preprint

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The universal chirality is the commonly accepted view of nature. Biological chirality is the distinct part of the more general phenomena. Following this view, all living organisms are characterized by the non-equilibrium state of their molecular constituents. From the thermodynamic perspective, the non-equilibrium state of biomolecular ensemble holds inevitable consequences being the substrate of spontaneous reactions directed to equilibrium (not associated with life) state. At the protein level, spontaneous biological reactions represent the natural part of proteins' post-translational modifications (PTMs). The essential contribution to the origin and maintenance of the non-equilibrium state belongs to prevalent bio-molecular chirality. Correspondently, spontaneous PTMs such as racemization and glycation, working against life-supporting prevalent chirality, are known as the significant determinants of protein misfolding, dysfunctions, and aggregation. Accumulation of aberrant protein during life-span allows consideration of time-dependent spontaneous racemization and glycation as protein aging. Spontaneous PTMs of proteins is occurring in the interaction with other forms of enzymatic and non-enzymatic PTMs. In this review, we are considering the contribution of spontaneous racemization and non-enzymatic glycosylation to protein aging.

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“…NS of homochiral proteins (trapped in a local energy minimum) is thermodynamically only relatively stable and, therefore, is prone to further spontaneous relaxation to aberrant conformation and aggregative states. Such spontaneous processes can be triggered by amino acid (AAs) racemization [ 23 , 24 ]. Spontaneous racemization is known as one of the unavoidable degrading forces of the functional state of proteins.…”

Section: Introductionmentioning

confidence: 99%

Fundamental Clock of Biological Aging: Convergence of Molecular, Neurodegenerative, Cognitive and Psychiatric Pathways: Non-Equilibrium Thermodynamics Meet Psychology

Dyakin

Dyakina-Fagnano

McIntire

et al. 2021

IJMS

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In humans, age-associated degrading changes, widely observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psychological abilities, and memory. Cross-talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, genome, proteome, and lipidome instability are widely recognized as the primary causal factors in aging. We narrow attention to the roles of protein aging linked to prevalent amino acids chirality, enzymatic and spontaneous (non-enzymatic) post-translational modifications (PTMs SP), and non-equilibrium phase transitions. The homochirality of protein synthesis, resulting in the steady-state non-equilibrium condition of protein structure, makes them prone to multiple types of enzymatic and spontaneous PTMs, including racemization and isomerization. Spontaneous racemization leads to the loss of the balanced prevalent chirality. Advanced biological aging related to irreversible PTMs SP has been associated with the nontrivial interplay between somatic (molecular aging) and mental (psychological aging) health conditions. Through stress response systems (SRS), the environmental and psychological stressors contribute to the age-associated “collapse” of protein homochirality. The role of prevalent protein chirality and entropy of protein folding in biological aging is mainly overlooked. In a more generalized context, the time-dependent shift from enzymatic to the non-enzymatic transformation of biochirality might represent an important and yet underappreciated hallmark of aging. We provide the experimental arguments in support of the racemization theory of aging.

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Racemization hypothesis of neurodegeneration (RHND)

Cited by 3 publications

References 0 publications

Arrow of Time, Entropy, and Protein Folding: Holistic View on Biochirality

Arrow of Time, Entropy, and Protein Folding: Holistic View on Biochirality

Spontaneous Determinants of Protein Aging Mini Review

Fundamental Clock of Biological Aging: Convergence of Molecular, Neurodegenerative, Cognitive and Psychiatric Pathways: Non-Equilibrium Thermodynamics Meet Psychology

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