The Application of Clinical Genetics (Mar 2021)
The Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia
Abstract
Daniel W Sirkis,1 Luke W Bonham,1,2 Jennifer S Yokoyama1,2 1Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, 94158, USA; 2Department of Radiology & Biomedical Imaging, University of California San Francisco, San Francisco, CA, 94158, USACorrespondence: Jennifer S YokoyamaMemory and Aging Center, Department of Neurology, University of California San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USATel +1 415 476-5565Fax +1 415 502-7588Email [email protected]: Microglia play a critical but poorly understood role in promoting white-matter homeostasis. In this review, we leverage advances in human genetics and mouse models of leukodystrophies to delineate our current knowledge and identify outstanding questions regarding the impact of microglia on central nervous system white matter. We first focus on the role of pathogenic mutations in genes, such as TREM2, TYROBP, and CSF1R, that cause leukodystrophies in which the primary deficit is thought to originate in microglia. We next discuss recent advances in disorders such as adrenoleukodystrophy and Krabbe disease, in which microglia play an increasingly recognized role. We conclude by reviewing the roles of GRN and related genes, such as TMEM106B, PSAP, and SORT1, that affect microglial biology and associate with several types of disease, including multiple leukodystrophies as well as forms of frontotemporal dementia (FTD) presenting with white-matter abnormalities. Taken together, mouse and human data support the notion that loss of microglia-facilitated white-matter homeostasis plays an important role in the development of leukodystrophies and suggest novel mechanisms contributing to FTD.Keywords: leukodystrophies, leukoencephalopathies, frontotemporal dementia, white matter, microglia, progranulin
