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

  title={A pivotal role of matrix metalloproteinase‐3 activity in dopaminergic neuronal degeneration via microglial activation},
  author={Yoon-Seong Kim and Dong-Hee Choi and Michelle L. Block and Stefan Lorenzl and Lichuan Yang and Youn Jung Kim and Shuei Sugama and Byung Pil Cho and Onyou Hwang and Susan E. Browne and Soo Yul Kim and Jau-Shyong Hong and M. Flint Beal and Tong Hyub Joh},
  journal={The FASEB Journal},
  pages={179 - 187}
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… 

A novel intracellular role of matrix metalloproteinase‐3 during apoptosis of dopaminergic cells

ActMMP‐3 seems to have a novel intracellular role in apoptotic DArgic cells and this finding provides an insight into the pathogenesis of Parkinson’s disease.

DJ-1 cleavage by matrix metalloproteinase 3 mediates oxidative stress-induced dopaminergic cell death.

The data suggest thatDJ-1 is fragmented by the intracellular MMP3 in response to cell stress, abolishing the protective role of DJ-1 against oxidative damage, and this contributes to the pathogenesis of PD.

Matrix metalloproteinase‐3 in the central nervous system: a look on the bright side

MMP‐3 is correlated with neuronal migration and neurite outgrowth and guidance in the developing CNS and contributes to synaptic plasticity and learning in the adult CNS, which might support remyelination and neuroprotection in the injured or diseased CNS.

Downregulation of miR‐7116‐5p in microglia by MPP+ sensitizes TNF‐α production to induce dopaminergic neuron damage

The studies suggest that MPP+ suppresses miR‐7116‐5p level in microglia and potentiates TNF‐α production and inflammatory responses to contribute to DA neuron damage.

Doxycycline is Neuroprotective Against Nigral Dopaminergic Degeneration by a Dual Mechanism Involving MMP-3

Doxycycline showed neuroprotective effect on DAergic system both in vitro and in vivo and this appeared to derive from anti-apoptotic and anti-inflammatory mechanisms involving downregulation of MMP-3.

Apoptosis Signal-Regulating Kinase 1 Mediates MPTP Toxicity and Regulates Glial Activation

It is found that MPTP administration to wild-type mice activates ASK1 in the midbrain, and inhibiting this kinase is a plausible therapeutic strategy for protecting dopamine neurons in PD.

Matrix Metalloproteinase-3 Causes Dopaminergic Neuronal Death through Nox1-Regenerated Oxidative Stress

Novel molecular mechanisms underlying oxidative stress-mediated dopaminergic neuronal death are established in which MMP3 activation is a key upstream event that leads to mitochondrial ROS, Nox1 induction and eventual dopamine neuronal death.

Microglial involvement in brain physiopathology: in vitro studies using rat primary cultures

The microglial M1/M2 phenotype in transgenic rats (McGill-R-Thy1-APP) which reproduce extensively the Alzheimer’s-like amyloid pathology is characterized and could represent a target for manipulation aimed at promoting neuroprotection in brain diseases.



Matrix Metalloproteinase-3: A Novel Signaling Proteinase from Apoptotic Neuronal Cells That Activates Microglia

The results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration in degenerative human brain disorders, such as Parkinson's disease.

Critical Role for Microglial NADPH Oxidase in Rotenone-Induced Degeneration of Dopaminergic Neurons

Results indicated that the greatly enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-derived superoxide from activated microglia, and suggested that microglial NAD PH oxidase may be a promising target for PD treatment.

Microglial activation‐mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease

This is the first report that microglial activation induced by chronic exposure to inflammagen was capable of inducing a delayed and selective degeneration of nigral dopaminergic neurons and thatmicroglia‐originated free radicals play a pivotal role in dopaminationergic neurotoxicity in this inflammation‐mediated model of PD.

Molecular consequences of activated microglia in the brain: overactivation induces apoptosis

Microglia, the resident immune cells in the brain, play a pivotal role in immune surveillance, host defense, and tissue repair in the CNS. In response to immunological challenges, microglia readily

Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's disease

This study lends strong support for a multifactorial etiology of PD and provides clues for therapeutic interventions by demonstrating the synergistic neurotoxicity of MPTP and LPS.

Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease

It is shown that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP.

Matrix metalloproteinase-9 is elevated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice

Results indicate that MMP-9 is induced after MPTP application in mice and that pharmacologic inhibition of MMPs protects against MPTP neurotoxicity.

NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

A critical role for NADPH-oxidase is supported in the pathogenesis of PD and it is suggested that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.

Presence of reactive microglia in monkey substantia nigra years after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration

Evidence of chronic neuroinflammation years after MPTP exposure is similar to that previously reported in humans and could have important implications regarding the cause of Parkinson's disease and possible approaches to therapy.

Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine exposure

Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case, suggesting that a time‐limited insult to the nigrostriatal system can set in motion a self‐perpetuating process of neurodegeneration.