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10.3390/cells12070993
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Article

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

by
Dar-Shong Lin
1,2,*,
Yu-Wen Huang
3,
Tsung-Han Lee
3,
Lung Chang
1,2,
Zon-Darr Huang
3,
Tsu-Yen Wu
3,
Tuan-Jen Wang
4 and
Che-Sheng Ho
2,5,*
1
Department of Pediatrics, MacKay Memorial Hospital, Taipei 10449, Taiwan
2
Department of Medicine, MacKay Medical College, New Taipei 25245, Taiwan
3
Department of Medical Research, MacKay Memorial Hospital, Taipei 10449, Taiwan
4
Department of Laboratory Medicine, MacKay Memorial Hospital, Taipei 10449, Taiwan
5
Department of Neurology, MacKay Children’s Hospital, Taipei 10449, Taiwan
*
Authors to whom correspondence should be addressed.
Cells 2023, 12(7), 993; https://doi.org/10.3390/cells12070993
Submission received: 20 January 2023 / Revised: 23 February 2023 / Accepted: 22 March 2023 / Published: 24 March 2023
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lysosomal Storage Disorders)
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Abstract

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.
Keywords: psychosine; globoid cell leukodystrophy; Krabbe disease; demyelination; autophagy; ubiquitin-proteasome system; neuroinflammation psychosine; globoid cell leukodystrophy; Krabbe disease; demyelination; autophagy; ubiquitin-proteasome system; neuroinflammation

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MDPI and ACS Style

Lin, D.-S.; Huang, Y.-W.; Lee, T.-H.; Chang, L.; Huang, Z.-D.; Wu, T.-Y.; Wang, T.-J.; Ho, C.-S. Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy. Cells 2023, 12, 993. https://doi.org/10.3390/cells12070993

AMA Style

Lin D-S, Huang Y-W, Lee T-H, Chang L, Huang Z-D, Wu T-Y, Wang T-J, Ho C-S. Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy. Cells. 2023; 12(7):993. https://doi.org/10.3390/cells12070993

Chicago/Turabian Style

Lin, Dar-Shong, Yu-Wen Huang, Tsung-Han Lee, Lung Chang, Zon-Darr Huang, Tsu-Yen Wu, Tuan-Jen Wang, and Che-Sheng Ho. 2023. "Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy" Cells 12, no. 7: 993. https://doi.org/10.3390/cells12070993

APA Style

Lin, D.-S., Huang, Y.-W., Lee, T.-H., Chang, L., Huang, Z.-D., Wu, T.-Y., Wang, T.-J., & Ho, C.-S. (2023). Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy. Cells, 12(7), 993. https://doi.org/10.3390/cells12070993

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