Neurodegenerative diseases and oxidative stress.
Oxidative stress is now recognized as accountable for redox regulation involving reactive oxygen species (ROS) and reactive nitrogen species (RNS). Its role is pivotal for the modulation of critical cellular functions, notably for neurons astrocytes and microglia, such as apoptosis program activation, and ion transport, calcium mobilization, involved in excitotoxicity. Excitotoxicity and apoptosis are the two main causes of neuronal death. The role of mitochondria in apoptosis is crucial. Multiple apoptotic pathways emanate from the mitochondria. The respiratory chain of mitochondria that by oxidative phosphorylation, is the fount of cellular energy, i.e. ATP synthesis, is responsible for most of ROS and notably the first produced, superoxide anion (O(2)(;-)). Mitochondrial dysfunction, i.e. cell energy impairment, apoptosis and overproduction of ROS, is a final common pathogenic mechanism in aging and in neurodegenerative disease such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Nitric oxide (NO(;)), an RNS, which can be produced by three isoforms of NO-synthase in brain, plays a prominent role. The research on the genetics of inherited forms notably ALS, AD, PD, has improved our understanding of the pathobiology of the sporadic forms of neurodegenerative diseases or of aging of the brain. ROS and RNS, i.e. oxidative stress, are not the origin of neuronal death. The cascade of events that leads to neurons, death is complex. In addition to mitochondrial dysfunction (apoptosis), excitotoxicity, oxidative stress (inflammation), the mechanisms from gene to disease involve also protein misfolding leading to aggregates and proteasome dysfunction on ubiquinited material.
Emerit
J
J
Service des Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitié-Salpêtrière, 47, boulevard de l'Hôpital, 75651 cedex 13, Paris, France. emerit@wanadoo.fr
Edeas
M
M
Bricaire
F
F
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*