Cell-autonomous expression of the acid hydrolase galactocerebrosidase.
Proc Natl Acad Sci U S A
; 117(16): 9032-9041, 2020 04 21.
Article
en En
| MEDLINE
| ID: mdl-32253319
ABSTRACT
Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as "cross-correction." Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GALCLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células de Schwann
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Proteínas Recombinantes de Fusión
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Galactosilceramidasa
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Leucodistrofia de Células Globoides
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Lisosomas
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2020
Tipo del documento:
Article