Galactosylceramidase deficiency and pathological abnormalities in cerebral white matter of Krabbe disease

Therapeutic depletion of CD8+ T-cells prevents myelin pathology in Globoid Cell Leukodystrophy

“…One CD8+ T-cell population showed a 9-fold increase in CD8+ T cells in twi mouse brain compared to wt (Fig. 4C, 4D, fig S8B), further validating our earlier findings and consistent with the reported presence of elevated T cells in twi and human GLD CNS (8)(9)(10)(11)14). Transcriptomic analysis of this profoundly increased CD8+ T cell population confirmed an activated cytotoxic T-cell phenotype indicated by increased expression of cytotoxic markers including CD160, XCL1, GZMB, and CXCR6 (Fig.…”

“…Loss of function mutation in the enzyme galactocerebrosidase (GALC) in GLD leads to an accumulation of galactosylsphingosine (“psychosine”) which is known to contribute to the hallmarks of GLD neuropathology including neuroinflammation and demyelination ( 3, 4 ). Research has shown that neuroinflammation in GLD precedes demyelination ( 5–7 ), and we have confirmed evidence of CD8+ T-cells in human GLD brain, as well as identified comparable findings in naturally occurred GLD models in both dogs (fig S1A-S1D), and the twitcher mouse model ( 8–11 ). However, a functional role for CD8+ T cells had not been identified in this disease.…”

“…Research has shown that neuroinflammation in GLD precedes demyelination (5)(6)(7), and we have confirmed evidence of CD8+ T-cells in human GLD brain, as well as identified comparable findings in naturally occurred GLD models in both dogs (fig S1A -S1D), and the twitcher mouse model (8)(9)(10)(11). However, a functional role for CD8+ T cells had not been identified in this disease.…”

“…It is currently not known how the metabolic consequences of galc mutations in GLD result in the development of such a profound immunological response. CD8+ T cells are a predominant cytotoxic lymphocyte population found in human neuroinflammatory diseases affecting central nervous system white matter, including GLD ( 11, 16–18 ). Accordingly, additional study on the genesis of CD8+ T cell responses in this disease model may contribute to our fundamental understanding of how these immunological responses may begin.…”

CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy

“…However, the functional role of CD8 + T cells was not examined in this study. Several additional histological studies have also identified the presence of increased CD8 + T cells in human GLD CNS ( Itoh et al, 2002 ; Iacono et al, 2022 ), further emphasizing that the role of T cells in GLD should be investigated.…”