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

Abstract

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.

Transthyretin Amyloid Cardiomyopathy: Impact of Transthyretin Amyloid Deposition in Myocardium on Cardiac Morphology and Function

“…TTR non-fibrillar aggregates induce a cytotoxic response that involves mitochondrial dysfunction, endoplasmic reticulum stress, and dysregulation of the Ca 2+ balance. Consequently, these cytotoxic responses may result in ROS accumulation and inflammation progression [ 17 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”

Transcriptome analysis of the zebrafishatoh7−/−Mutant,lakritz, highlights Atoh7‐dependent genetic networks with potential implications for human eye diseases

“…[97][98][99][100] The finding of smarca5 as an upregulated gene in the lakritz indicates the importance to address functional implications of this chromatin remodeling gene for atoh7-related eye disorders. Furthermore, the "neural retina development" Gene Ontology category encompassed the reportedly stress response genes hsp70.1(HSPA1L) 69 and mmp14 101 as significantly downregulated and upregulated, respectively, by the lakritz mutation. The crystallin related, heat shock Hsp70 family proteins are emerging as important regulators of RGC survival and regeneration as well as retinal vascular remodeling factors.…”

C1QA and C1QC modify age‐at‐onset in familial amyloid polyneuropathy patients

“…To explore other possible genetic factors that may modulate AO, we used a family centered approach and focused on candidate genes, C1QA and C1QC, which can affect functional pathways in the course of the disease. It is well recognized that inflammatory infiltrates are rarely seen in nerve biopsies, 26 but several authors found evidence of activation of inflammatory markers in the tissues of patients 27 and animal models 28,29 and even in the peripheral blood. 30 However, the primary or secondary role of these markers remains a matter of controversy.…”