M. LEPRAE-INDUCED CONTACT-DEPENDENT DEMYELINATION

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DESCRIPTION (provided by applicant): Demyelination, which leads to prolonged neurological disability, is one of the central pathologic conditions that is shared by leprosy and many neurodegenerative diseases with unknown etiology, such as multiple sclerosis (MS) and Guillain-Barr syndrome {GBS). However, molecular basis of demyelination is largely unknown. We propose that there are common themes at the onset of demyelination process among these classical and infectious neurodegenerative diseases. One of the well-known examples of infectious neurodegenerative diseases with peripheral nerve demyelination is leprosy, which is caused by the non-toxic bacterium, Mycobacterium leprae. Our recent studies have shown that M. leprae can be used as a model to dissect the early molecular events of demyelination. We found that the binding of M. leprae or its cell wall components to myelinating Schwann cell-axon units is sufficient to induce significant demyelination in a contact-dependent manner, which does not require immune responses. However, the mechanism of such myelin damage, which represents initial events of demyelination, is unknown. To study these, we used previously established rat myelinating Schwann cell-neuron co-culture system and Rag-1 -/- knockout mice as in vitro and in vivo models respectively. Microarray analysis using Affymetrix rat and mouse GeneChips with cRNA prepared from myelinating Schwann cell-neuron-co-cultures and the Sciatic nerves iromRag-1-/- knockout mice infected with M. leprae, we showed (i) significant up-regulation of genes for major signaling proteins, and (ii) down-regulation of genes for myelin and synaptic proteins and voltage-gated ion channels. We propose that the attachment of M. leprae to the receptors/molecules on Schwann cell-axon units rapidly induce strong signaling that influence the activation of downstream transcription factors and gene expression that eventually lead to myelin damage. To investigate these, we will study the following: (1) Temporal gene expression at the onset of and during M. teprae-induced demyelination, (2) Characterization of signaling pathways and transcriptional activation in early demyelination, and (3) Identification and characterization of non-laminin receptors as M. leprae targets for induction of signaling and demyelination. These studies will provide novel insights into the early molecular events of demyelination and neuronal dysfunctions at receptor, signaling, transcriptional and gene levels, and will aid in developing new diagnostics and therapeutics for nerve injuries both in leprosy and other neurodegenerative diseases such as MS and GBS.