c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease

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dc.contributor.authorMarin, Tamara
dc.contributor.authorDulcey, Andres E.
dc.contributor.authorCampos, Fabian
dc.contributor.authorde la Fuente, Catalina
dc.contributor.authorAcuna, Mariana
dc.contributor.authorCastro, Juan
dc.contributor.authorPinto, Claudio
dc.contributor.authorYanez, Maria Jose
dc.contributor.authorCortez, Cristian
dc.contributor.authorMcGrath, David W.
dc.contributor.authorSaez, Pablo J.
dc.contributor.authorGorshkov, Kirill
dc.contributor.authorZheng, Wei
dc.contributor.authorSouthall, Noel
dc.contributor.authorCarmo-Fonseca, Maria
dc.contributor.authorMarugan, Juan
dc.contributor.authorAlvarez, Alejandra R.
dc.contributor.authorZanlungo, Silvana
dc.date.accessioned2025-01-20T21:09:15Z
dc.date.available2025-01-20T21:09:15Z
dc.date.issued2022
dc.description.abstractNiemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lowers sphingomyelin accumulation in NPA patient fibroblasts and NPA neuronal models and 3) chronic treatment with nilotinib and neurotinib, two c-Abl inhibitors with differences in blood-brain barrier penetrance and target binding mode, show further benefits. While nilotinib treatment reduces neuronal death in the cerebellum and improves locomotor functions, neurotinib decreases glial activation, neuronal disorganization, and loss in hippocampus and cortex, as well as the cognitive decline of NPA mice. Our results support the participation of c-Abl signaling in NPA neurodegeneration and autophagy-lysosomal alterations, supporting the potential use of c-Abl inhibitors for the clinical treatment of NPA patients.
dc.fuente.origenWOS
dc.identifier.doi10.3389/fcell.2022.844297
dc.identifier.issn2296-634X
dc.identifier.urihttps://doi.org/10.3389/fcell.2022.844297
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/93520
dc.identifier.wosidWOS:000781160800001
dc.language.isoen
dc.revistaFrontiers in cell and developmental biology
dc.rightsacceso restringido
dc.subjectNiemann-Pick disease
dc.subjectneurodegeneration
dc.subjectc-Abl kinase
dc.subjectautophay-lysosomal pathway
dc.subjectlysosomal storage disorder (LSD)
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlec-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease
dc.typeartículo
dc.volumen10
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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