Racemization hypothesis of neurodegeneration (RHND)

Authors: Victor Vasilyevich Dyakin, Abel Lajtha, Nika Victorovna Dyakina‐Fagnano

Published: 2020-12-07

Abstract

AbstractBackgroundBiochirality, evident in the homochirality of deoxyribonucleic acid (DNA) and the prevalent chirality of amino acids (AAs) in a bilateral organism, represents a challenge for modern biochemistry and neuroscience. Attention to the spontaneous post translational racemization allow revealing the link between protein aging, cell aging, and decline of cognitive functions should be highlighted.MethodAnalytical review of current advances in the molecular biology, biophysics, and neuroscience.ResultAt the protein level, biochirality is closely associated with various post‐translational modifications (PTMs), which support the dynamic balance of the prevalent chirality of enzymes and their substrates. This review posits a racemization hypothesis of neurodegeneration (RHND) that focuses on the distinct forms of the aberrant PTMs, which critically impact enzymes‐substrate interaction named spontaneous racemization. From a thermodynamic perspective, the collapse of homochirality by racemization is the result of a conformational non‐equilibrium phase transition. At the cellular level, the concept of non‐equilibrium phase transitions (PhTs) is relevant to the biophysics of PTMs, physiology of membrane‐less organelles (MLO), and intrinsically disordered proteins (IDPs). MLOs, containing IDPs, represent coherent structures with distinct protein dynamics and biological functions. MLOs containing IDPs are implicated in protein folding and aberrant protein conformation leading to aggregation diseases. Spontaneous, non‐enzymatic PTMs within MLOs represent the internal determinants of protein aging, cell aging and age‐related diseases. Recently it has been shown that the racemization of the serine (Ser) residue occurs (preferably) in the flexible (unstructured or intrinsically disordered) regions of proteins.ConclusionThe amyloid cascade hypothesis in Alzheimer’s disease (AD) needs to be reconciled with the failure of numerous Aβ targeting drug therapies in clinical trials. In our view, both neuroscience and thermodynamic advances are necessary for addressing the brain region, cell type, and age‐dependent racemization processes that critically influence nervous system functions. The link between protein aging, cell aging, and decline of cognitive functions should be highlighted. The chiral non‐equilibrium phase transitions (PhTs) concomitant with the protein misfolding and aggregation, evident in an increasing number of experimental results, convince as to introduce the RHND.