Multiple sclerosis (MS) a common disease of the central nervous system (CNS) with a direct link to immune system function. MS is characterized as an autoimmune disease, in which the immune system mounts an inappropriate immune response against the CNS. Specifically, self-reactive T lymphocytes are thought to drive disease pathogenesis by inducing an inflammatory response that results in plaque formation characterized by accumulations of immune cells in areas of demyelination. In addition to plaque formation, it has become clear that MS clinical symptoms also result from damage to neurons. Axonal loss has also been reported. A variety of immune-mediated mechanisms have been indicated in neuronal damage, but none have been specifically confirmed in MS. We have recently discovered that self-reactive T cells produce a secreted protein that induces neuronal injury by destabilization of microtubule -tubulin in axons. Axonal function and survival is dependent upon fast axonal transport of neurotransmitters and growth factors in the axons along microtubules. Thus the destablization of microtubules puts the neuron at risk for death. We have named this soluble factor Microtubule Axonal Destablizer or MAD. Using an experimental autoimmune encephalomyelitis (EAE) acute mouse model of MS, we have been able to demonstrate axonal dysfunction consistent with microtubule destablization in the CNS. This neuronal dysfunction was observed early in disease and was reversed upon recovery from EAE clinical disease. In order to further study the mechanisms of how MAD induces neuronal dysfunction, we need to purify and identify the MAD protein. This knowledge is required in order to determine if MAD or its signaling pathways can be targeted as a therapy for MS and other neurodegenerative diseases. Since MAD is an immune-mediated protein that directly affects neuronal function, its identification will facilitate our understanding of functional links between the immune and nervous systems. The hypothesis driving the current proposal is: Activated lymphocytes responding to CNS inflammation secrete a protein (MAD) that directly destabilizes axonal -tubulin causing a transport defect that directly results in MS clinical symptoms. The overall goal of this project is to determine whether MAD is a potential therapeutic target for MS or and other neurodegenerative disease. However, to ultimately achieve this goal, we must purify and identify MAD. This is the single aim of this application.
Many diseases of the nervous system, including multiple sclerosis, are often associated with damage to neurons resulting in disability. We have uncovered a novel mechanism whereby cells of the immune system directly mediate neuronal dysfunction. The goal of this proposal is to purify and identify the protein responsible for the neuronal damage such that it can be investigated as a new therapeutic target for the treatment of neurodegenerative diseases in subsequent studies.
| Miller, Nichole M; Shriver, Leah P; Bodiga, Vijaya L et al. (2013) Lymphocytes with cytotoxic activity induce rapid microtubule axonal destabilization independently and before signs of neuronal death. ASN Neuro 5:e00105 |
