Type-2 alkenes mediate synaptotoxicity in neurodegenerative diseases.
Synaptic dysfunction appears to be an early pathogenic event in Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease. Although the molecular mechanism of this synaptotoxicity is not known, evidence suggests that these diseases are characterized by a common pathophysiological cascade involving oxidative stress, lipid peroxidation and the subsequent liberation of alpha,beta-unsaturated carbonyl derivatives such as acrolein and 4-hydroxy-2-nonenal (HNE). A diverse body of in vivo and in vitro data have shown that these soft electrophilic chemicals can cause nerve terminal damage by forming Michael-type adducts with nucleophilic sulfhydryl groups on presynaptic proteins. Therefore, the endogenous generation of acrolein and HNE in oxidatively stressed neurons of certain brain regions might be mechanistically related to the synaptotoxicity associated with neurodegenerative conditions. In addition, acrolein and HNE are members of a large class of structurally related chemicals known as the type-2 alkenes. Chemicals in this class (e.g., acrylamide, methylvinyl ketone, and methyl acrylate) are pervasive pollutants in human environments and new research has shown that these alpha,beta-unsaturated carbonyl derivatives are also toxic to nerve terminals. In this review, we provide evidence that the regional synaptotoxicity, which develops during the early stages of many neurodegenerative diseases, is mediated by endogenous generation of acrolein and HNE. Based on a presumed common nerve terminal site of action, we propose that the onset and progression of this neuropathogenic process is accelerated by environmental exposure to other type-2 alkenes.
Lopachin
Richard M
RM
Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Moses Research Tower 7, 111 East 2210th Street, Bronx, NY 10467-2490, United States. lopachin@aecom.yu.edu
Gavin
Terrence
T
Barber
David S
DS
D000475:Alkenes / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D000818:Animals; D006801:Humans; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000473:pathology*; D013569:Synapses / Q000187:drug effects* / Q000473:pathology*
D000475:Alkenes