title: 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 the 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.
authors: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA 91766, USA.
authors: Guanghong
authors: G
authors: Liao
authors: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA 91766, USA.
authors: Zhuangjun
authors: Z
authors: Wang
authors: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA 91766, USA.
authors: Erik
authors: E
authors: Lee
authors: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA 91766, USA.
authors: Stephanie
authors: S
authors: Moreno
authors: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA 91766, USA.
authors: Omar
authors: O
authors: Abuelnasr
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, 701 E. Second Street, Pomona, CA 91766, USA.
authors: Michel
authors: M
authors: Baudry
authors: Department of Basic Medical Sciences, COMP, Western University of Health Sciences, 701 E. Second Street, Pomona, CA 91766, USA. Electronic address: xbi@westernu.edu.
authors: Xiaoning
authors: X
authors: Bi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001369:Axons / Q000473:pathology*; D002531:Cerebellum / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000473:pathology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D053508:Matrix Metalloproteinase 12
keywords: Axonal degeneration; EMMPRIN; MMP-12; MMP-9; Myelination; Niemann–Pick type C; siRNA knockdown