Neuroinflammation in the progression of axonal degeneration in PMD

Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in the myelin protein – proteolipid protein-1 (PLP1). PMD patients have a progressive loss of coordination, motor abilities, and intellectual function. Axon degeneration, a major cause of disability in inherited and acquired neurological disorders, occurs in PMD patients, especially those with mutations that result in loss or reduction of PLP. We hypothesize that dysmyelination caused by mutations in PLP induces microglia activation and a proinflammatory feed-forward loop that is deleterious for axonal health, and that neuroinflammation represents a viable therapeutic target to preserve motor function and axon integrity in PMD. We will test our hypothesis using a knock-in mouse generated by Dr. Franca Cambi, that carries deletion of the intronic splicing enhancer (ISE) of PLP (PLP-ISEdel), associated with a mild form of PMD. In a recent collaborative project with Professor Cambi, we found strong and progressive microglia activation in the PLP-ISEdel mice. This has led to the intriguing hypothesis that microglia activation may participate in a feed-forward mechanism to accelerate the progressive loss of axon integrity and neuron function. We have proposed to test our hypothesis that microglia activation contributes to the pathological progression of PMD by the following two aims: AIM 1: Elucidate the temporal onset of microglia activation and proinflammatory cytokine levels as it relates to axonal injury and motor impairments in the PLP-ISEdel mouse model of PMD. AIM 2: Determine if axonal pathology and motor behavior impairments can be rescued in PLP-ISEdel mice by using the glia cytokine inhibitor – MW-151. The significance and translational potential of this project is very high. If our studies are successful, we will have defined a key mechanism underlying natural history of the pathophysiology progression in PMD, as well as a promising therapeutic candidate for the treatment of PMD