Plasmin-mediated degradation of laminin gamma-1 is critical for ethanol-induced neurodegeneration.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Our data identify laminin gamma-1 as a novel target to combat neurodegeneration.
Skrzypiec
Anna E
AE
Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom.
Maiya
Rajani
R
Chen
Zulin
Z
Pawlak
Robert
R
Strickland
Sidney
S
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D018929:Cell Culture Techniques; D019070:Cell Lineage; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000009:adverse effects* / Q000378:metabolism; D005341:Fibrinolysin / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism*; D010958:Plasminogen / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*
D007797:Laminin; C089141:laminin gamma 1; D000431:Ethanol; D010958:Plasminogen; D007770:L-Lactate Dehydrogenase; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin