Abstract
The loss of protein homeostasis that has been associated with aging leads to altered levels and conformational instability of proteins, which tend to form toxic aggregates. In particular, brain aging presents characteristic patterns of misfolded oligomers, primarily constituted of β-amyloid (Aβ), tau, and α-synuclein (α-syn), which can accumulate in neuronal membranes or extracellular compartments. Such aging-related proteins can also reach peripheral compartments, thus suggesting the possibility to monitor their accumulation in more accessible fluids. In this respect, we have demonstrated that α-syn forms detectable hetero-aggregates with Aβ or tau in red blood cells (RBCs) of healthy subjects. In particular, α-syn levels and its heteromeric interactions are modulated by plasma antioxidant capability (AOC), which increases in turn with physical activity. In order to understand if a specific distribution of misfolded proteins can occur in other blood cells, a cohort of human subjects was enrolled to establish a correlation among AOC, the level of physical exercise and the concentrations of aging-related proteins in platelets. The healthy subjects were divided depending on their level of physical exercise (i.e., athletes and sedentary subjects) and their age (young and older subjects). Herein, aging-related proteins (i.e., α-syn, tau and Aβ) were confirmed to be present in human platelets. Among such proteins, platelet tau concentration was demonstrated to decrease in athletes, while α-syn and Aβ did not correlate with physical exercise. For the first time, α-syn was shown to directly interact with Aβ and tau in platelets, forming detectable hetero-complexes. Interestingly, α-syn interaction with tau was inversely related to plasma AOC and to the level of physical activity. These results suggested that α-syn heterocomplexes, particularly with tau, could represent novel indicators to monitor aging-related proteins in platelets.
Highlights
IntroductionAging is characterized by a gradual decline of the protein homeostasis (proteostasis) network, which affects the levels and conformational stability of proteins (Díaz-Villanueva et al, 2015; Labbadia and Morimoto, 2015), causing the formation of misfolded and toxic aggregates (Lindner and Demarez, 2009; Morimoto and Cuervo, 2014; Tan et al, 2014; Labbadia and Morimoto, 2015), and cell death.Misfolded and oligomeric proteins appear to spread through the brain in characteristic, with robust evidence for the increase of beta amyloid− (Aβ), tau, and α-synuclein (α-syn) (Jucker and Walker, 2013; Goedert, 2015; Giacomelli et al, 2017)
Western blotting analysis was used to investigate the presence of α-syn, tau and Aβ proteins in platelets isolated from healthy subjects
The main findings of this work are the follows: (i) α-syn declined in older subjects, whereas Aβ directly correlated with increasing age; (ii) total α-syn and Aβ concentrations showed an inverse correlation with antioxidant capability (AOC) toward peroxynitrite derivatives in elderly and sedentary subjects, respectively; (iii) tau levels decreased in athletes; (iv) α-syn directly interacted with Aβ and tau in platelets; (v) α-syn interaction with tau was inversely related to peroxynitrite AOC and to the level of physical activity
Summary
Aging is characterized by a gradual decline of the protein homeostasis (proteostasis) network, which affects the levels and conformational stability of proteins (Díaz-Villanueva et al, 2015; Labbadia and Morimoto, 2015), causing the formation of misfolded and toxic aggregates (Lindner and Demarez, 2009; Morimoto and Cuervo, 2014; Tan et al, 2014; Labbadia and Morimoto, 2015), and cell death.Misfolded and oligomeric proteins appear to spread through the brain in characteristic, with robust evidence for the increase of beta amyloid− (Aβ), tau, and α-synuclein (α-syn) (Jucker and Walker, 2013; Goedert, 2015; Giacomelli et al, 2017). The occurrence of hybrid oligomers (“heteroaggregates”) has been shown in both patients’ brains and cellular models (Parnetti et al, 2013; Sengupta et al, 2015; Andersen et al, 2017; Daniele et al, 2017; Giacomelli et al, 2017) In this respect, the levels of the so called “aging-related proteins” have been monitored recently in human red blood cells (RBCs), where α-syn has been shown to interact with Aβ or tau healthy subjects (Daniele et al, 2017). ROS have been demonstrate to enhance the aggregation, of neurodegeneration-related proteins that, in turn, may interact with transition metals or other components to generate further ROS (Snead and Eliezer, 2014; Xiang et al, 2015)
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