Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease
Krabbe disease (KD) is a childhood leukodystrophy with no cure currently available. KD is due to a deficiency of a lysosomal enzyme called galactosyl-ceramidase (GALC) and is characterized by the accumulation in the nervous system of the sphingolipid psychosine (PSY), whose cytotoxic molecular mecha...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996119301238 |
| _version_ | 1818651647066243072 |
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| author | Ambra Del Grosso Lucia Angella Ilaria Tonazzini Aldo Moscardini Nadia Giordano Matteo Caleo Silvia Rocchiccioli Marco Cecchini |
| author_facet | Ambra Del Grosso Lucia Angella Ilaria Tonazzini Aldo Moscardini Nadia Giordano Matteo Caleo Silvia Rocchiccioli Marco Cecchini |
| author_sort | Ambra Del Grosso |
| collection | DOAJ |
| description | Krabbe disease (KD) is a childhood leukodystrophy with no cure currently available. KD is due to a deficiency of a lysosomal enzyme called galactosyl-ceramidase (GALC) and is characterized by the accumulation in the nervous system of the sphingolipid psychosine (PSY), whose cytotoxic molecular mechanism is not fully known yet.Here, we study the expression of some fundamental autophagy markers (LC3, p62, and Beclin-1) in a KD murine model [the twitcher (TWI) mouse] by immunohistochemistry and Western blot. Moreover, the autophagy molecular process is also shown in primary fibroblasts from TWI and WT mice, with and without PSY treatment. Data demonstrate that large p62 cytoplasmic aggregates are present in the brain of both early and late symptomatic TWI mice. p62 expression is also upregulated in TWI sciatic nerves compared to that measured for WT nerves. In vitro data suggest that this effect might not be fully PSY-driven. Finally, we investigate in vitro the capability of autophagy inducers (Rapamycin, RAP and Resveratrol, RESV) to reinstate the WT phenotype in TWI cells. We show that RAP administration can partially restore the autophagy markers levels, while RESV cannot, indicating a line along which new therapeutic approaches can be developed. |
| first_indexed | 2024-12-17T02:09:26Z |
| format | Article |
| id | doaj.art-1c810ca212dc476c95d215ca1a0f0afe |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:09:26Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-1c810ca212dc476c95d215ca1a0f0afe2022-12-21T22:07:36ZengElsevierNeurobiology of Disease1095-953X2019-09-01129195207Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe diseaseAmbra Del Grosso0Lucia Angella1Ilaria Tonazzini2Aldo Moscardini3Nadia Giordano4Matteo Caleo5Silvia Rocchiccioli6Marco Cecchini7NEST, Isituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, ItalyNEST, Isituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, ItalyNEST, Isituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, ItalyNEST, Isituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, ItalyScuola Normale Superiore, Piazza dei Cavalieri 7, 56127 Pisa, Italy; CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, ItalyCNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy; Department of Biomedical Sciences, University of Padua, 35121 Padova, ItalyInstitute of Clinical Physiology-CNR, Via Giuseppe Moruzzi 1, Pisa 56124, ItalyNEST, Isituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy; Corresponding author.Krabbe disease (KD) is a childhood leukodystrophy with no cure currently available. KD is due to a deficiency of a lysosomal enzyme called galactosyl-ceramidase (GALC) and is characterized by the accumulation in the nervous system of the sphingolipid psychosine (PSY), whose cytotoxic molecular mechanism is not fully known yet.Here, we study the expression of some fundamental autophagy markers (LC3, p62, and Beclin-1) in a KD murine model [the twitcher (TWI) mouse] by immunohistochemistry and Western blot. Moreover, the autophagy molecular process is also shown in primary fibroblasts from TWI and WT mice, with and without PSY treatment. Data demonstrate that large p62 cytoplasmic aggregates are present in the brain of both early and late symptomatic TWI mice. p62 expression is also upregulated in TWI sciatic nerves compared to that measured for WT nerves. In vitro data suggest that this effect might not be fully PSY-driven. Finally, we investigate in vitro the capability of autophagy inducers (Rapamycin, RAP and Resveratrol, RESV) to reinstate the WT phenotype in TWI cells. We show that RAP administration can partially restore the autophagy markers levels, while RESV cannot, indicating a line along which new therapeutic approaches can be developed.http://www.sciencedirect.com/science/article/pii/S0969996119301238Globoid cell leukodystrophyGLDKrabbe diseaseKDAutophagyPsychosine |
| spellingShingle | Ambra Del Grosso Lucia Angella Ilaria Tonazzini Aldo Moscardini Nadia Giordano Matteo Caleo Silvia Rocchiccioli Marco Cecchini Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease Neurobiology of Disease Globoid cell leukodystrophy GLD Krabbe disease KD Autophagy Psychosine |
| title | Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease |
| title_full | Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease |
| title_fullStr | Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease |
| title_full_unstemmed | Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease |
| title_short | Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease |
| title_sort | dysregulated autophagy as a new aspect of the molecular pathogenesis of krabbe disease |
| topic | Globoid cell leukodystrophy GLD Krabbe disease KD Autophagy Psychosine |
| url | http://www.sciencedirect.com/science/article/pii/S0969996119301238 |
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