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Lookup NU author(s): Searlait Thom, Luca Gosse, Dr Daniel ErskineORCiD
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Krabbe disease, also named globoid cell (GC) leukodystrophy (GLD) for its distinct lipid-laden macrophages, is a severe leukodystrophy caused by galactosylceramidase (GALC) mutations. Hematopoietic stem cell transplant (HSCT) ameliorates disease and is associated with central nervous system (CNS) engraftment of GALC+ donor macrophages. Yet, the role of macrophages in GLD pathophysiology and HSCT remains unclear. Using single-cell sequencing, we revealed early interferon response signatures that preceded progressively severe macrophage dyshomeostasis and identified a molecular signature of GCs, which we validated in human brain specimens. Genetic depletion and direct microglia replacement by CNS monocyte injection rapidly replaced >80% of endogenous microglia with healthy macrophages in the twitcher (GalcW355∗) mouse model of GLD. Perinatal microglia replacement completely normalized transcriptional signatures, rescued histopathology, and doubled average survival. Overall, we uncovered distinct forms of microglial dysfunction and evidence that direct, CNS-limited microglia replacement improves a monogenic neurodegenerative disease, identifying a promising therapeutic target.
Author(s): Aisenberg WH, O'Brien CA, Sangster M, Yaqoob F, Zhang Y, Temsamrit B, Thom S, Gosse L, Chaluvadi S, Elfayomi B, Lee G, Polam V, Levitt EM, Liu G, Lombroso SI, Nemec KM, Clowry G, Nieves C, Rawat P, Church E, Martinez D, Shoffler C, Kancheva D, Petucci C, Taylor D, Kofler J, Erskine D, Movahedi K, Bennett ML, Bennett FC
Publication type: Article
Publication status: Published
Journal: Immunity
Year: 2025
Volume: 58
Issue: 5
Pages: p1254-1268.e9
Print publication date: 13/05/2025
Online publication date: 30/04/2025
Acceptance date: 26/03/2025
ISSN (print): 1074-7613
ISSN (electronic): 1097-4180
URL: https://doi.org/10.1016/j.immuni.2025.03.019
DOI: 10.1016/j.immuni.2025.03.019
PubMed id: 40311614
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