Analysis of a mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

? DESCRIPTION (provided by applicant): Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), is a rare, autosomal dominant, neurodegenerative disorder that is characterized by adult-onset dementia with motor impairments and epilepsy. ALSP encompasses two similar diseases previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD). The disease is caused by dominant mutations in the colony stimulating factor-1 receptor gene (CSF1R) resulting in loss of function, or of expression, of one allele. We have identified the heterozygous Csf1r+/- mouse as a model of ALSP. Csf1r+/- mice exhibit cognitive and sensorimotor deficits and depression- and anxiety- like behavior characteristic of early ALSP. MRI of Csf1r+/- brains reveals similarities to the radiologic changes in ALSP. Histopathological examination indicates neuronal loss, neuronal degeneration with presence of axonal spheroids and microgliosis, that are characteristic of the human disease. It is not known whether developmental deficits contribute to ALSP, nor whether loss of a single copy of the Csf1r gene in neurons and/or microglia is most critical for disease pathogenesis. Furthermore, there are no effective treatment options for ALSP. Our mouse model of ALSP will enable these questions to be addressed, early detection methods identified and novel treatment approaches instituted. The Overall Aim is to utilize our mouse model of ALSP to determine the contributions of development, aging, microglial and neuronal lineages to disease pathogenesis and to explore therapeutic strategies based on these findings. In Specific Aim 1, we will determine the nature and cellular origins of developmental abnormalities in Csf1r haploinsufficient mice. The nature and timing of the appearance of histopathologic changes in the developing brains of Csf1r+/- mice, will be examined, the role of Csf1r haploinsufficiency in the microglial and/or neuronal lineages assessed and regulation by inappropriately elevated cytokines elucidated. In Specific Aim 2, we will determine the necessity of microglial and/or neuronal regulation by the CSF-1R for disease development by genetic deletion of a single Csf1r allele in the microglial and/or neuronal lineages of mice. In Specific Aim 3, we will identify targets for the treatment of ALSP. The proposed studies are relevant not only for our understanding of ALSP, but also with respect to other neurodegenerative disorders in which neuronal cell survival and microglial function are critical. They will also directly contribute to our understanding of the roles of CSF-1R signaling n neuronal development and the regulation of microglia.