Fig. 6

Chronic Psychological Stress: Proteinopathy and Synaptic Plasticity. During chronic stress (depicted by dark blue arrows), prolonged activation of GRs inhibits Ca²⁺/Calmodulin dependent kinases IIα and can lead to DNA hypermethylation that supresses gene transcription and protein synthesis (epigenetic memory effect). Severe stress can also reduce the expression of the stathmin that is related to the cellular skeleton, mitosis, and synaptic plasticity, which in turn, relates to poor learning and apoptosis. As well, chronic stress/single prolonged stress can increase SNARE complex formation but alter neurotransmitters fusion that relates to excitotoxicity and pathological accumulation of aggregated proteins. Alteration of the protein-kinase dynamics increases risk for proteinopathy and, in turn, depression and neurodegenerative disorders. See Fig. 4 for the path [1]–[4]. cAMP, cyclic AMP; CREB, cAMP response element-binding protein; ERK, extracellular regulated kinase, aka mitogen-activated protein kinase (MAPK); GR, glucocorticoid receptors; GRE, glucocorticoid response elements; PO₃², phosphorylation