Adult Onset Leukoencephalopathy with Axonal Spheroid and Pigmented Glia (ALSP) is a neurodegenerative disorder leading to presenile dementia. While devastating, our lack of understanding of the disease has hindered the development of effective treatments. ALSP is characterized by ablation of the white matter, cortical atrophy in the frontal and parietal lobes, epileptic seizures as well as spastic paraplegia. Importantly, genome wide linkage analyses have linked mutations in the kinase domain of Colony stimulating factor 1 receptor (CSF1R) as a causative agent towards development of ALSP. CSF1R is primarily expressed by microglia in the homeostatic brain highlighting the potential for microglia to be critically involved in ALSP pathogenesis. Interestingly, a CSF1R haploinsufficient (CSF1R+/-) mouse model of ALSP presents with increased number of microglia similar to a multitude of neurodegenerative disorders which also present with increases in microglial number. Preliminary studies comparing Wild-type (WT) and CSF1R+/- mice revealed performance deficits in behavioral tasks of CSF1R+/- mice. Immunohistochemical analyses found alterations to protein expressions in CSF1R+/- mice ? increased levels of neuronal Lamp1 (one of the top differentially expressed genes in our RNAsequencing data) and decreased number of synaptic elements Bassoon, Synaptophysin and Sv2A. As it stands, these data, and more, hint at microglia playing some role in mediating the disease. What that role is, however, remains to be discovered. In this proposal I seek to 1) create a timecourse of microglial proliferation and apoptosis during early postnatal development and adulthood to investigate the mechanism for increased microglia densities 2) characterize microglia transcriptional profiles during these time points and 3) identify whether microglia are involved in disease pathogenesis by creating mouse lines that have CSF1R heterozygosity specifically in microglia and neurons as recent evidence has revealed CSF1R expression in neuronal subtypes as well as neural progenitor cells. Collectively, this proposal will elucidate the role of microglial CSF1R signaling in the development of ALSP pathology, providing insight into novel mechanisms governing neurodegeneration and ALSP progression and setting the groundwork for future studies that could lead to the development of disease modifying therapies.
Adult Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) is a progressive neurodegenerative disease that results in dementia, epilepsy, and ultimately, early death. Recent genetic analyses link mutations in the kinase domain of Colony stimulating factor receptor 1 (CSF1R), a receptor primarily expressed by microglia in the brain, to disease development. Thus, understanding the role microglia play in the development of ALSP will be crucial to create effective disease-modifying therapies.
