Enhanced expression of matrix metalloproteinase-12 contributes to Npc1 deficiency-induced axonal degeneration

Abstract

Niemann-Pick type C (NPC) disease is a genetic disorder associated with intracellular cholesterol accumulation in brain and other organs, and neurodegeneration is generally believed to be the fatal cause of the disease. In view of the emerging role of matrix metalloproteinase-12 (MMP-12) in neuronal injury, we investigated its expression and potential roles in axonal degeneration in Npc1−/− mouse brain. Microarray and quantitative real-time reversed transcription PCR analysis indicated a marked increase in MMP-12 mRNA levels in cerebellum of 3 week-old Npc1−/− mice, as compared to wild-type littermates. Western blots showed that the ratio of mature MMP-12 over pro-MMP-12 was significantly increased in cerebellum of Npc1−/−, as compared to wild-type mice. Immunohistochemical studies confirmed that MMP-12 expression was increased, especially in the cell bodies of Purkinje neurons in Npc1−/− mice. Neuritic growth was significantly reduced by Npc1 siRNA knockdown in nerve growth factor-differentiated PC-12 cells, and this effect was completely reversed by treatment with an MMP-12 specific inhibitor. Furthermore, in vivo experiments showed that chronic treatment with the MMP-12 inhibitor ameliorated Npc1 deficiency-induced axonal pathology in the striatum. Our results indicate that abnormal neuronal expression of MMP-12 may contribute to axonal degeneration in NPC disease, thus providing a potential novel target for treatment.

A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models

“…Here, we demonstrate that specific inhibition of MMP-12 is capable to protect RGCs against cell death occurring after ONC. Previous in vivo experiments also showed that chronic treatment with MMP-12 inhibitor ameliorated Npc1 deficiency-induced axonal pathology in the striatum [ 48 ]. In the same line, MMP-12 deficiency protected against spinal cord injury, a neuroprotective effect suggested to relate to a decreased permeability of the blood-spinal barrier and reduced microglial activation and macrophage infiltration in MMP-12 null mice [ 4 ].…”

HuR promotes the molecular signature and phenotype of activated microglia: Implications for amyotrophic lateral sclerosis and other neurodegenerative diseases

“…A therapeutic potential for MMP inhibition in ALS was shown in the mtSOD1 mouse where administration of an MMP inhibitor early in the disease course prolonged survival and improved motor function (Lorenzl et al, ). Other deleterious effects linked to MMP‐12 include myelin proteolysis, axonal damage, and activation/upregulation of other potentially toxic MMPs (e.g., MMP‐2, 3, and 9) (Lagente, Le Quement, & Boichot, ; Liao et al, ; Matsumoto et al, ; Shiryaev et al, ). This may explain the improved outcome of stroke and spinal cord injury in mice where MMP‐12 was deleted (Chelluboina et al, ; Wells et al, ).…”

Serum proteomic approach for differentiation of frail and non-frail elderly

“…MMP-12, a human macrophage metalloelastase, is a 54kDa proenzyme which was first recognized as a protein secreted by inflammatory macrophages [27]. MMP-12 has been found to be associated with inflammatory skin disorders [28], atherosclerosis [29] and some central nervous system diseases [30]. It is reported that this protein releases TNFα which initiate a cascade of inflammatory pathway eventually [31].…”