The Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia

Figures & data

Table 1 Progranulin (GRN)-Related Genes Associated Directly or Indirectly with Frontotemporal Dementia (FTD) and Inherited White-Matter Disorders

Gene Symbol	Expressed in Microglia?	Enriched in Microglia?	Affects GRN Trafficking or Circulating Levels?	Genetic Association with FTD?	Genetic Association with White-Matter Disease?	Selected References
GRN	Yes	Yes	N/A	Causative	Subset of FTLD-GRN shows WMH	[^Citation17^–^Citation20,Citation89^–^Citation91,Citation93]
TMEM106B	Yes	No	Circulating levels	Risk modifier	Hypomyelinating leukodystrophy	[^Citation15,Citation20,Citation94^–^Citation97,Citation102^–^Citation105]
PSAP	Yes	Yes	Trafficking and circulating levels	Not yet	Metachromatic leukodystrophy; other sphingolipidoses	[^Citation16,Citation111,Citation115,Citation118]
SORT1	Yes	No	Trafficking and circulating levels	Risk factor	Subset of FTD cases harboring rare SORT1 variants present with WMH	[^Citation22,Citation119]

Notes: The GRN-associated genes TMEM106B, PSAP, and SORT1 are associated with circulating progranulin levels and in some cases also influence progranulin sorting. Most of the above genes are genetically associated with FTD as well as various forms of leukodystrophy or white-matter hyperintensities in the context of frontotemporal lobar degeneration pathology. These findings, when considered collectively, suggest that variation in the PSAP locus may ultimately be identified as a risk factor for FTD. Moreover, the findings suggest that progranulin-associated proteins may impart risk for FTD by modulating microglial function and white-matter resilience over the lifespan.

Abbreviations: FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; GRN, progranulin; PSAP, prosaposin; SORT1, sortilin; TMEM106B, transmembrane protein 106B; WMH, white-matter hyperintensities.

Figure 1 Distinct pathogenic mutations and microglial phenotypes are associated with white-matter disorders with highly variable ages of neurological symptom onset. White-matter diseases and the major microglial phenotypes they may be associated with are ordered according to their typical, approximate age range of onset. The characteristic microglial phenotypes listed are from histopathological studies and/or relevant mouse models of disease; see main text for references. Ages of neurological symptom onset can range from prenatal for type I interferonopathy associated with USP18 deficiency and congenital absence (or near-absence) of microglia due to homozygous mutations in CSF1R, up to the 50s–70s for some cases of frontotemporal lobar degeneration with white-matter hyperintensities associated with pathogenic GRN mutations. Created with BioRender.com.

Abbreviations: ABCD1, ATP-binding cassette D1; ALSP, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; CSF1R, colony-stimulating factor 1 receptor; FTLD, frontotemporal lobar degeneration; GRN, progranulin; HDLS, hereditary diffuse leukoencephalopathy with axonal spheroids; POLD, pigmented orthochromatic leukodystrophy; TMEM106B, transmembrane protein 106B; TORCH, toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus; TREM2, triggering receptor expressed on myeloid cells 2; TYROBP, TYRO protein tyrosine kinase-binding protein; USP18, ubiquitin-specific protease 18.

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