A pivotal role of matrix metalloproteinase‐3 activity in dopaminergic neuronal degeneration via microglial activation

Abstract

Recent studies have demonstrated that activated microglia play an important role in dopamine (DA) neuronal degeneration in Parkinson disease (PD) by generating NADPH-oxidase (NADPHO)-derived superoxide. However, the molecular mechanisms that underlie microglial activation in DA cell death are still disputed. We report here that matrix metalloproteinase-3 (MMP-3) was newly induced and activated in stressed DA cells, and the active form of MMP-3 (actMMP-3) was released into the medium. The released actMMP-3, as well as catalytically active recombinant MMP-3 (cMMP-3) led to microglial activation and superoxide generation in microglia and enhanced DA cell death. cMMP-3 caused DA cell death in mesencephalic neuron-glia mixed culture of wild-type (WT) mice, but this was attenuated in the culture of NADPHO subunit null mice (gp91(phox-/-)), suggesting that NADPHO mediated the cMMP-3-induced microglial production of superoxide and DA cell death. Furthermore, in the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-injected animal model of PD, nigrostriatal DA neuronal degeneration, microglial activation, and superoxide generation were largely attenuated in MMP-3-/- mice. These results indicate that actMMP-3 released from stressed DA neurons is responsible for microglial activation and generation of NADPHO-derived superoxide and eventually enhances nigrostriatal DA neuronal degeneration. Our results could lead to a novel therapeutic approach to PD.

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

“…MMP-3 released by dying neurons activates microglia, further contributing to neurodegeneration (Kim et al 2007) along with MMP-9 (Woo et al 2008). Altered gelatinase expression in the SN of post-mortem brains of PD patients was first reported by Lorenzl et al (2002), according to whom no alteration in MMP-9 protein and activity levels were observed compared to age-matched controls.…”

“…MMP-2 and -9 are highly expressed in the brain in physiological conditions, and MMP-9 and -3 are significantly up-regulated in several brain pathologies, including PD (Lorenzl et al 2002, Kim et al 2007Choi et al 2008), highlighting them as possible therapeutic targets (Leonardo and Pennypacker 2009). Specific MMP inhibitors have been developed; however, indiscriminate block of this enzymatic activity is a dangerous ground, since MMPs play different roles depending on the type of pathology and time of activation.…”

Macrophages regulate tumor necrosis factor-α expression in adipocytes through the secretion of matrix metalloproteinase-3

“…31 Moreover, activated MMP-3 is present in the nuclear compartment of malignant and nontransformed hepatocytes, and is associated with the onset of apoptosis. 32 These studies suggested a novel function of MMP-3 as a signaling molecule active for intracellular functions.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Recent studies provided molecular details to the understanding of the neuroinflammaotry component in PD. It has been shown that the products secreted by damaged neurons ( [251,121]) aggregated alpha-synuclein or environmental toxins such as LPS are recognised by the macrophage antigen complex 1, Mac-1, a PRR expressed on microglia cells; in turn, Mac-1 activation is crucial for activation of NADPH oxidase, a membrane-bound enzyme that catalyses the production of superoxide anions, which are released in the extracellular space, and generates intracellular ROS, well known triggers of the inflammatory response ( [18,122,223,264]). NADPH oxidase is associated with neurodegenerative disorders and neuronal damage; it is activated in the brains of patients with PD [252].…”