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.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), is a rare genetic, neurodegenerative disease, that is characterized by dementia with motor impairments and epilepsy that develops in men and women at a median age of 42 years, with an average duration of 5 years, culminating in death of the patient. In livin patients, it is almost always misdiagnosed as Alzheimer's disease, or similar neurodegenerative disorder. ALSP encompasses two similar diseases previously known as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmentary orthochromatic leukodystrophy (POLD). The disease was recently shown to be caused by loss of function of one copy of the gene encoding colony stimulating factor-1 receptor (CSF-1R). This receptor mediates signals from two protein hormones CSF- 1 and IL-34, that we have shown are made by different subsets of mature neurons. CSF-1 and IL-34 control the survival, development and multiplication of two types of brain cells, microglia and neurons. Microglia are non-neuronal brain-resident cells that play critical roles in brain development, support brain function and mediate recovery from infection and injury. It is not known whether developmental deficits contribute to ALSP, nor whether the loss of one copy of the CSF-1R gene in neurons, or the microglia, is most critical for disease development. Furthermore, there are no effective treatment options for ALSP. We have developed a mouse model of ALSP by deleting one copy of the CSF-1R gene. This model, which mimics the human disease, will enable these questions to be addressed and novel treatment approaches to be tested. The proposed studies are highly relevant, not only for our understanding of ALSP, but also to other neurodegenerative disorders, in which neuron survival and microglial function are critical.
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