Nitric Oxide and Sphingolipids as Modulators of Apoptosis and Autophagy: Functional Implications in Neurodegenerative Chronic Brain Disorders

Aberrant regulation of the apoptosis and autophagy machineries is a central abnormality in most human neurodegenerative disorders characterized by progressive dysfunction and death of neuronal and glial cells. Both in central and peripheral nervous systems, cell death can be either apoptotic or autophagic, depending on the cellular setting and inducing stressor. However, while some mixed phenotypes have been reported, apoptosis and autophagy ultimately may develop in mutually exclusive ways and appear to inhibit each other. Generation of the pleiotropic sphingolipid mediator ceramide is a key event in many cellular processes including survival and death, in which also the short-lived gaseous messenger nitric oxide (NO) plays a crucial role. Much progress has been made in understanding the crosstalk among the NO and the sphingolipid pathway, with its multiple feedback controls which have important implications in neurophysiological and neuropathological processes. Strikingly these mediators impact on both apoptosis and autophagy. What we provide here are details on how NOand sphingolipid-dependent signaling impact on chronic brain disorders, i.e., Alzheimer’s, Parkinson’s, and Huntington’s diseases; we also describe how their crosstalk and regulation of autophagy and apoptosis may play a significant role in determining the pathogenic evolution. The evidence we report suggest that targeting the NO and sphingolipid signalling pathways may ultimately be exploited in therapeutic perspective. However, defining how this integrated pathway balances towards beneficial vs. toxic effects appears to be complex and needs being resolved to identify suitable therapeutic targets and strategies. NITRIC OXIDE AND SPHINGOLIPIDS AS MODULATORS OF APOPTOSIS AND AUTOPHAGY: FUNCTIONAL IMPLICATIONS IN NEURODEGENERATIVE CHRONIC BRAIN DISORDERS