Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease?

Abstract

Exposure to environmental toxins is associated with a variety of age-related diseases including cancer and neurodegeneration. For example, in Parkinson's disease (PD), chronic environmental exposure to certain toxins has been linked to the age-related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti-cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence-associated secretory phenotype (SASP; that is the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age-related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. On the basis of recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder.

Fig. 1

Induction and detection of cellular senescence. Multiple stressors induce cellular senescence in cell culture and in vivo. The over-expression of cell-cycle inhibitors, such as p16 and p21, irreversibly blocks cell proliferation. Activation of oncogenes and telomeric dysfunction eventually cause DNA damage and cell-cycle arrest. Oxidative stress and other stress signals, such as mitochondrial dysfunction, can induce cellular senescence through various mechanisms such as via induction of p53 or DNA damage. Senescent cells acquire a specific phenotype characterized by increased cell size, expression of the lysosomal enzyme B-galactosidase, loss of proliferation, formation of permanent DNA damage foci (DNA segments with chromatin alterations reinforcing senescence or SCARS), chromatin remodelling (SAHF) and induction of a secretory phenotype (SASP).