Nature Medicine
- 12, 961 - 966 (2006)
Published online: 30 July 2006; Corrected online: 17 August 06 | doi:10.1038/nm1433
There is a Corrigendum (September 2006) associated with this Letter.
ErbB2 receptor tyrosine kinase signaling mediates early demyelination induced by leprosy bacilliNikos Tapinos, Makoto Ohnishi & Anura Rambukkana
The Rockefeller University, Bronk Building, Room 501, Box 172, 1230 York Avenue, New York, New York 10021, USA.
Correspondence should be addressed to Anura Rambukkana rambuka@rockefeller.edu Demyelination is a common pathologic feature in many neurodegenerative diseases including infection with leprosy-causing Mycobacterium leprae
1,
2,
3. 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 demyelination4,
5 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 phosphorylation6,
7,
8,
9. 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 antibody9,
10, 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
