Matrix metalloproteinases (MMPs) are matrix-degrading enzymes involved in diverse homeostatic and pathological processes. Several MMPs are expressed within the CNS and serve important normal and pathological functions during development and adulthood. An early and major pathological effect of MMP activity after cerebral ischemia is opening of the blood-brain barrier (BBB). More recent work demonstrates emerging roles for MMPs and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), in the regulation of neuronal cell death. In addition, MMPs and TIMPs are likely to play important roles during the repair phases of cerebral ischemia, particularly during angiogenesis and reestablishment of cerebral blood flow. This review attempts to elucidate how MMPs and TIMPs may provide detrimental or beneficial actions during the injury and repair processes after cerebral ischemia. These processes will have important implications for therapies using MMP inhibitors in stroke.

Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and DNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the DNp73 isoform. Mice lacking DNp73 (DNp73 -/-mice) are viable and fertile but display signs of neurodegeneration. Cells from DNp73 -/-mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in DNp73-/-cells, we discovered a completely new role for DNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that DNp73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of DNp73 expression show enhanced resistance to chemotherapy.[Keywords: p73; p53; neurodegeneration; DNA damage response; apoptosis] Supplemental material is available at http://www.genesdev.org.

The genetic mechanisms that regulate neurodegeneration are only poorly understood. We show that the loss of one allele of the p53 family member, p73, makes mice susceptible to neurodegeneration as a consequence of aging or Alzheimer's disease (AD). Behavioral analyses demonstrated that old, but not young, p73+/- mice displayed reduced motor and cognitive function, CNS atrophy, and neuronal degeneration. Unexpectedly, brains of aged p73+/- mice demonstrated dramatic accumulations of phospho-tau (P-tau)-positive filaments. Moreover, when crossed to a mouse model of AD expressing a mutant amyloid precursor protein, brains of these mice showed neuronal degeneration and early and robust formation of tangle-like structures containing P-tau. The increase in P-tau was likely mediated by JNK; in p73+/- neurons, the activity of the p73 target JNK was enhanced, and JNK regulated P-tau levels. Thus, p73 is essential for preventing neurodegeneration, and haploinsufficiency for p73 may be a susceptibility factor for AD and other neurodegenerative disorders.

Metalloproteinase activity at the cell surface influences cellular sensitivity to extrinsic death vs. survival signals in a variety of cell types, through proteolytic shedding of cell surface signalling molecules. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a unique natural metalloproteinase inhibitor that plays a pro-apoptotic role through its ability to inhibit metalloproteinases that proteolytically cleave death receptors and their ligands from the cell surface. To study the convergence of metalloproteinase activity and death receptor signalling in neurons, we established an in vitro model of neuronal apoptosis utilizing the chemotherapeutic drug, doxorubicin (Dox). Primary cultures established from embryonic rat cerebral cortices displayed robust and selective neuronal apoptosis in response to Dox, an effect that was dependent on the activation of the death receptor, Fas. We demonstrate that both TIMP-3 and matrix metalloproteinase-3 (MMP-3) are constitutively expressed by primary cortical neurons in culture, and selectively modulated Fas-mediated neuronal apoptosis induced by Dox. Metalloproteinase inhibition by TIMP-3 was found to be necessary for Dox-induced neuronal death, whereas addition of active MMP-3 markedly attenuated apoptosis and diminished Fas-Fas ligand interaction at the cell surface. These observations implicate a physiological role for the balance of TIMP-3 and MMP-3 activity at the neuronal surface in regulating death receptor sensitivity. The convergence of metalloproteinase activity and death receptor signalling at the cell surface may influence neuronal cell death vs. survival decisions.