A dual role for Integrin α6β4 in modulating hereditary neuropathy with liability to pressure palsies. Issue 3 (13th February 2018)

• Record Type: Journal Article
• Authors: Poitelon, Yannick; Matafora, Vittoria; Silvestri, Nicholas; Zambroni, Desirée; McGarry, Claire; Serghany, Nora; Rush, Thomas; Vizzuso, Domenica; Court, Felipe A.; Bachi, Angela; Wrabetz, Lawrence; Feltri, Maria Laura
• Is Part Of: Journal of neurochemistry. Volume 145:Issue 3(2018)
• Page Start: 245
• Page End: 257
• Publication Date: 2018-02-13
• Subjects: HNPP -- Integrin β4 -- myelin -- peripheral nerve -- Pmp22 -- Schwann cells; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14295
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Peripheral myelin protein 22 (PMP22) is a component of compact myelin in the peripheral nervous system. The amount of PMP22 in myelin is tightly regulated, and PMP22 over or under‐expression cause Charcot‐Marie‐Tooth 1A (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP). Despite the importance of PMP22, its function remains largely unknown. It was reported that PMP22 interacts with the β4 subunit of the laminin receptor α6β4 integrin, suggesting that α6β4 integrin and laminins may contribute to the pathogenesis of CMT1A or HNPP. Here we asked if the lack of α6β4 integrin in Schwann cells influences myelin stability in the HNPP mouse model. Our data indicate that PMP22 and β4 integrin may not interact directly in myelinating Schwann cells, however, ablating β4 integrin delays the formation of tomacula, a characteristic feature of HNPP. In contrast, ablation of integrin β4 worsens nerve conduction velocities and non‐compact myelin organization in HNPP animals. This study demonstrates that indirect interactions between an extracellular matrix receptor and a myelin protein influence the stability and function of myelinated fibers. Abstract : Laminin receptor integrin α6β4 modulates peripheral myelin protein 22 (PMP22) neuropathy. In this study, we employed biochemical and genetic studies to shed light on the relationship between PMP22 and signaling from the Schwann cell extracellular matrix. We demonstrate that ablation of β4 integrin delays the progression of Hereditary Neuropathy with Pressure Palsy (HNPP), but also causes a reduction in the speed of action potential propagation in HNPP animals. These findings suggest that in HNPP, integrin α6β4 has opposing effects on two distinct pathomechanisms, i.e. the formation of tomacula and the propagation of action potentials.