New CMT 1A research in affected nerves

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1: J Neurochem 2002 Nov;83(4):885-94

Matrix metalloproteinase mediated degradation of basement membrane

proteins in Trembler J neuropathy nerves.

Misko A, Ferguson T, Notterpek L.

Department of Neuroscience, College of Medicine, McKnight Brain

Institute of the University of Florida, Gainesville, Florida, USA.

A single point mutation in peripheral myelin protein 22 (pmp22) of the

Trembler-J (TrJ) mouse models the human peripheral neuropathy,

Charcot-Marie-Tooth disease type 1 A (CMT1A). An unexplored aspect of

this disease is the gradual remodeling of the extracellular matrix in

affected nerves.

To elucidate the mechanism responsible for these changes, the levels of

the extracellular matrix molecules laminin, collagen IV, and fibronectin

were determined. In TrJ nerves, laminin is modestly increased while

full-length forms of collagen IV and fibronectin are decreased. Matrix

metalloproteinases (MMPs) are known to degrade

multiple matrix molecules; therefore, nerves were assayed for MMP-2 and

MMP-9 proteins. In neuropathy nerves, elevated levels of MMP-2 and MMP-9

were detected on western blots, and gelatin zymography confirmed the

up-regulation of gelatinalytic activity in affected samples.

Immunostaining studies revealed an increase in the numbers of MMP-2- and

MMP-9-expressing cells in TrJ nerves. Cell type-specific immunolabeling

showed that infiltrating macrophages are a significant source of both

MMP-2 and MMP-9. Finally, the degradation of exogenous collagen IV by

TrJ nerve lysates was prevented with a specific MMP inhibitor. Together

these observations suggest that infiltration by

MMP-expressing macrophages contributes to the remodeling of the TrJ

nerve matrix.