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

 描述（由申请方提供）：伴有轴突球状体和色素性神经胶质的成人发作性白质脑病（ALSP）是一种罕见的常染色体显性遗传神经退行性疾病，其特征为成人发作性痴呆伴运动障碍和癫痫。ALSP包括两种类似的疾病，以前称为遗传性弥漫性白质脑病伴轴突球体（HDLS）和家族性色素性正染性脑白质营养不良（POLD）。这种疾病是由殖民地刺激因子-1受体基因（CSF 1 R）的显性突变引起的，导致一个等位基因的功能或表达丧失。我们已经确定了杂合子Csf 1 r +/-小鼠作为ALSP的模型。Csf 1 r +/-小鼠表现出认知和感觉运动缺陷以及早期ALSP的抑郁和焦虑样行为特征。Csf 1 r +/-脑的MRI显示与ALSP的放射学改变相似。组织学检查表明神经元丢失、神经元变性伴轴突球体和小胶质细胞增生，这是人类疾病的特征。目前尚不清楚发育缺陷是否会导致ALSP，也不知道神经元和/或小胶质细胞中Csf 1 r基因的单拷贝丢失是否对疾病发病机制最关键。此外，对于ALSP没有有效的治疗选择。我们的ALSP小鼠模型将使这些问题得到解决，早期检测方法的确定和新的治疗方法的制定。 总体目标是利用我们的ALSP小鼠模型来确定发育、衰老、小胶质细胞和神经元谱系对疾病发病机制的贡献，并根据这些发现探索治疗策略。在具体目标1中，我们将确定Csf 1 r单倍不足小鼠发育异常的性质和细胞起源。将检查Csf 1 r +/-小鼠发育中脑组织病理学变化的性质和出现时间，评估Csf 1 r单倍不足在小胶质细胞和/或神经元谱系中的作用，并阐明不适当升高的细胞因子的调节作用。在具体目标2中，我们将通过在小鼠的小胶质细胞和/或神经元谱系中遗传缺失单个Csf 1 r等位基因来确定CSF-1 R对疾病发展的小胶质细胞和/或神经元调节的必要性。在具体目标3中，我们将确定治疗ALSP的靶点。 拟议的研究不仅与我们对ALSP的理解有关，而且与其他神经退行性疾病有关，其中神经元细胞存活和小胶质细胞功能至关重要。它们也将直接有助于我们理解CSF-1 R信号在神经元发育和小胶质细胞调节中的作用。

 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.