c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease
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c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease. / Marín, Tamara; Dulcey, Andrés E; Campos, Fabián; de la Fuente, Catalina; Acuña, Mariana; Castro, Juan; Pinto, Claudio; Yañez, María José; Cortez, Cristian; McGrath, David W; Sáez, Pablo J; Gorshkov, Kirill; Zheng, Wei; Southall, Noel; Carmo-Fonseca, Maria; Marugán, Juan; Alvarez, Alejandra R; Zanlungo, Silvana.
in: FRONT CELL DEV BIOL, Jahrgang 10, 844297, 2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - c-Abl Activation Linked to Autophagy-Lysosomal Dysfunction Contributes to Neurological Impairment in Niemann-Pick Type A Disease
AU - Marín, Tamara
AU - Dulcey, Andrés E
AU - Campos, Fabián
AU - de la Fuente, Catalina
AU - Acuña, Mariana
AU - Castro, Juan
AU - Pinto, Claudio
AU - Yañez, María José
AU - Cortez, Cristian
AU - McGrath, David W
AU - Sáez, Pablo J
AU - Gorshkov, Kirill
AU - Zheng, Wei
AU - Southall, Noel
AU - Carmo-Fonseca, Maria
AU - Marugán, Juan
AU - Alvarez, Alejandra R
AU - Zanlungo, Silvana
N1 - Copyright © 2022 Marín, Dulcey, Campos, de la Fuente, Acuña, Castro, Pinto, Yañez, Cortez, McGrath, Sáez, Gorshkov, Zheng, Southall, Carmo-Fonseca, Marugán, Alvarez and Zanlungo.
PY - 2022
Y1 - 2022
N2 - Niemann-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.
AB - Niemann-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.
U2 - 10.3389/fcell.2022.844297
DO - 10.3389/fcell.2022.844297
M3 - SCORING: Journal article
C2 - 35399514
VL - 10
JO - FRONT CELL DEV BIOL
JF - FRONT CELL DEV BIOL
SN - 2296-634X
M1 - 844297
ER -