MMP-14 overexpression correlates with the neurodegenerative process in familial amyloidotic polyneuropathy

• Main Authors: Diana Martins, João Moreira, Nádia Pereira Gonçalves, Maria João Saraiva
• Format: Article
• Language: English
• Published: The Company of Biologists 2017-10-01
• Series: Disease Models & Mechanisms
• Subjects: MMP-14; Familial amyloidotic polyneuropathy; Neurodegeneration; Neuroinflammation; Peripheral nervous system
• Online Access: http://dmm.biologists.org/content/10/10/1253
• ISSN: 1754-8403; 1754-8411

Levels of matrix metalloproteases (MMPs) can be differentially regulated in response to injury or neurological diseases. For instance, it is known that selective and short-term inhibition of MMP-14, a membrane-type 1 MMP, accelerates axon regeneration. Because axon growth and regeneration is impaired in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disorder characterized by misfolding and deposition of mutant transthyretin (TTR) in the peripheral nervous system (PNS), we presently investigated the expression levels and the potential role for MMP-14 in this condition. By using cell culture studies, a mouse model of disease and human clinical samples, we observed that MMP-14: (i) is overexpressed in FAP nerves, correlating with TTR deposition; (ii) is upregulated in sciatic nerves from a preclinical transgenic mouse model, increasing with TTR deposition; (iii) levels in the PNS and plasma are rescued upon treatment of mice with anakinra or TTR siRNA, drugs acting over the IL-1 signaling pathway or TTR liver synthesis, respectively; (iv) increases in Schwann cells upon incubation with amyloid-like aggregates; and, finally, (v) is increased in plasma of FAP patients, correlating with disease progression. These results highlight the relevance of MMP-14 in the pathophysiology of FAP, suggesting not only a potential role for this molecule as a novel biomarker for therapy follow up, but also as a new potential therapeutic target.