02835nas a2200505   4500000000100000008004100001260001300042653001200055653002700067653003800094653001500132653001400147653002000161653002700181653002500208653002700233653002200260653002200282653001500304653001100319653001200330653000900342653001900351653001500370653003900385653003900424653002500463653001300488653001600501653001300517653000900530653002100539653001800560653001800578653002400596653001600620100001400636700001400650700001700664245010200681300001000783490000700793520151500800022001402315       2006                            d  c2006 Aug10aAnimals10aAntibodies, Monoclonal10aAntibodies, Monoclonal, Humanized10aButadienes10aCOS Cells10aCells, Cultured10aCercopithecus aethiops10aCoculture Techniques10aDemyelinating Diseases10aEnzyme Activation10aEnzyme Inhibitors10aHela Cells10aHumans10aleprosy10aMice10aMice, Knockout10aMice, Nude10aMitogen-Activated Protein Kinase 110aMitogen-Activated Protein Kinase 310aMycobacterium leprae10aNitriles10aPyrimidines10aPyrroles10aRats10aReceptor, erbB-210aSchwann Cells10aSciatic Nerve10aSignal Transduction10aTrastuzumab1 aTapinos N1 aOhnishi M1 aRambukkana A00aErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilli.  a961-60 v123 a<p>Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae. Because of the long incubation time and highly complex disease pathogenesis, the management of nerve damage in leprosy, as in other demyelinating diseases, is extremely difficult. Therefore, an important challenge in therapeutic interventions is to identify the molecular events that occur in the early phase before the progression of the disease. Here we provide evidence that M. leprae-induced demyelination is a result of direct bacterial ligation to and activation of ErbB2 receptor tyrosine kinase (RTK) signaling without ErbB2-ErbB3 heterodimerization, a previously unknown mechanism that bypasses the neuregulin-ErbB3-mediated ErbB2 phosphorylation. MEK-dependent Erk1 and Erk2 (hereafter referred to as Erk1/2) signaling is identified as a downstream target of M. leprae-induced ErbB2 activation that mediates demyelination. Herceptin (trastuzumab), a therapeutic humanized ErbB2-specific antibody, inhibits M. leprae binding to and activation of ErbB2 and Erk1/2 in human primary Schwann cells, and the blockade of ErbB2 activity by the small molecule dual ErbB1-ErbB2 kinase inhibitor PKI-166 (ref. 11) effectively abrogates M. leprae-induced myelin damage in in vitro and in vivo models. These results may have implications for the design of ErbB2 RTK-based therapies for both leprosy nerve damage and other demyelinating neurodegenerative diseases.</p>  a1078-8956