Plasmin-Mediated Degradation of Laminin γ-1 Is Critical for Ethanol-Induced Neurodegeneration

Abstract

Alcoholism may result in severe neurological deficits and cognitive impairments. Many of the central effects of ethanol (EtOH) can be explained by upregulation of N-methyl-D-aspartate (NMDA) and downregulation of gamma-aminobutyric acid (GABA) A receptors (GABAA) in response to long-term EtOH consumption. Abrupt ethanol withdrawal (EW) may result in neuronal hyperexcitability leading to hallucinations, seizures, neurodegeneration, and sometimes death. Using a multidisciplinary approach in wild-type and genetically modified mice, we examined the contribution of the tissue plasminogen activator (tPA), plasminogen, and laminin to EW-induced cell death. Here we show that EW-induced neurodegeneration is mediated by the tPA/plasmin system. During EW, tPA is upregulated in the hippocampus and converts plasminogen to plasmin, which in turn degrades an extracellular matrix component laminin, leading to caspase-3-dependent cell death. Consequently, mice in which the tPA or plasminogen genes have been deleted do not show EW-induced laminin degradation, mitochondrial dysfunction, and neurodegeneration. Finally, we demonstrated that disruption of the hippocampal laminin gamma-1 renders the mice resistant to neurotoxic effects of EW. Our data identify laminin gamma-1 as a novel target to combat neurodegeneration.