Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy

• Published in: Cells (Basel, Switzerland) Switzerland), 2023-03, Vol.12 (7), p.993
• Main Authors: Lin, Dar-Shong, Huang, Yu-Wen, Lee, Tsung-Han, Chang, Lung, Huang, Zon-Darr, Wu, Tsu-Yen, Wang, Tuan-Jen, Ho, Che-Sheng
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antibodies; Astrocytes; Autophagy; Brain; Care and treatment; Clinical aspects; Demyelinating Diseases - drug therapy; Demyelination; Diagnosis; Dosage and administration; Galactosylceramidase - metabolism; Galactosylceramidase - therapeutic use; Gene mutations; Genetic aspects; Globoid cell leukodystrophy; Health aspects; Inflammation; Krabbe disease; Leukodystrophy; Leukodystrophy, Globoid Cell - drug therapy; Leukodystrophy, Globoid Cell - pathology; Lysosomal storage diseases; Mice; Microglia; Mutation; Myelination; Neurodegeneration; Neuroinflammatory Diseases; Pathogenesis; Proteasomes; Protein Aggregates; Proteins; psychosine; Rapamycin; Sirolimus - pharmacology; Sirolimus - therapeutic use; TOR protein; TOR Serine-Threonine Kinases; Ubiquitin; ubiquitin-proteasome system; Ubiquitins
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells12070993

We have shown in vivo and in vitro previously that psychosine causes dysfunction of autophagy and the ubiquitin-proteasome system underlying the pathogenesis of globoid cell leukodystrophy (GLD), a devastating lysosomal storage disease complicated by global demyelination. Here, we investigated the therapeutic efficacy of the mTOR inhibitor rapamycin in twitcher mice, a murine model of infantile GLD, in biochemical, histochemical, and clinical aspects. Administration of rapamycin to twitcher mice inhibited mTOR signaling in the brains, and significantly reduced the accumulation of insoluble ubiquitinated protein and the formation of ubiquitin aggregates. The astrocytes and microglia reactivity were attenuated in that reactive astrocytes, ameboid microglia, and globoid cells were reduced in the brains of rapamycin-treated twitcher mice. Furthermore, rapamycin improved the cortical myelination, neurite density, and rescued the network complexity in the cortex of twitcher mice. The therapeutic action of rapamycin on the pathology of the twitcher mice's brains prolonged the longevity of treated twitcher mice. Overall, these findings validate the therapeutic efficacy of rapamycin and highlight enhancing degradation of aggregates as a therapeutic strategy to modulate neuroinflammation, demyelination, and disease progression of GLD and other leukodystrophies associated with intracellular aggregates.