Nearly 30,000 US veterans are in the VA system being treated for Multiple Sclerosis (MS), a disabling disease that results in motor, sensory and cognitive dysfunction. There is no cure and treatments have limited efficacy. The overall goal of my lab is to provide a better understanding of the pathologic mechanisms that drive MS in order to develop new and better treatment options. MS is classically described as a demyelinating disorder where myelin loss is accompanied by axonal damage and irreversible neurological dysfunction. The prevail- ing theme is that axonal pathology in MS is consequential of chronic, long term demyelination. Although axon- al pathology clearly results from long term myelin loss, we propose that axonal pathology is also a primary event in MS that occurs early in disease and independent of demyelination. Supportive of this idea, axonal pathology is observed in both normal appearing white and grey matter; MS plaque load does not correlate with axonal loss; and axonal number is reduced in regions lacking myelin loss . In further support that axonal damage occurs independent of myelin loss and at very early stages of disease, we recently demonstrated that axonal pathology is indeed a primary event in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Our findings indicate that the axon initial segment (AIS), the myelin-bare, initial region of the ax- on responsible for action potential initiation and modulation, is specifically targeted by pro-inflammatory, reac- tive microglia in the absence of myelin loss resulting in subsequent AIS disruption. Moreover, we showed that anti-inflammatory treatment not only decreased microglial reactivity and microglia/AIS contact but also result- ed in amelioration of AIS disruption and in AIS restoration. The clinical relevance of these findings is support- ed by our most recent observations indicating that a similar AIS disruption also occurs in MS. Based on our findings, our working hypothesis is that in MS reactive microglia migrate toward injury cues and undergo mor- phologic change resulting in increased contact with the AIS facilitating the targeting of pro-inflammatory fac- tors promoting AIS disruption independent of demyelination. Moreover, we propose that inhibition of microglia response and interaction with the AIS will result in AIS preservation and restoration. Here, we present strong preliminary data that a novel isoform of the cell adhesion molecule neurofascin (Nfasc) mediates the microglia response in the MS model of EAE. Based on our findings and known functions of other Nfasc isoforms, we predict that microglia-specific ablation of Nfasc will 1. inhibit microglial migration, surveillance and cytokine secretion by disrupting actin dynamics and 2. result in structural and functional AIS preservation in EAE.
Multiple sclerosis is a devastating disease that inflicts sensory, motor and cognitive deficits on thousands of US veterans. Currently, there is no cure and the available therapies have variable results. MS is classically described as a demyelinating disease; However, more recent work has demonstrated that much of the irre- versible functional loss associated with this disease results from pathology of the nerve cell. Although nerve cell damage is now being investigated, it is being studied strictly as a consequence of chronic demyelination. Our previous work showed that the nerve cell is a primary target of attack and implicated the resident brain immune cells known as microglia as the facilitator of the attack. Here, we will investigate a novel factor that is may be critical for this attack and determine if this factor can be a therapeutic target for disease amelioration.
| Benusa, S D; George, N M; Sword, B A et al. (2017) Acute neuroinflammation induces AIS structural plasticity in a NOX2-dependent manner. J Neuroinflammation 14:116 |
| Otani, Yoshinori; Yermakov, Leonid M; Dupree, Jeffrey L et al. (2017) Chronic peripheral nerve compression disrupts paranodal axoglial junctions. Muscle Nerve 55:544-554 |
