Tamara Marín1, Andrés E. Dulcey2, Fabián Campos1, Catalina de la Fuente3, Mariana Acuña1,4, Juan Castro1, Claudio Pinto3, María José Yañez5, Cristian Cortez6, David W. McGrath7, Pablo J. Sáez7, Kirill Gorshkov2, Wei Zheng2, Noel Southall2, Maria Carmo-Fonseca8, Juan Marugán2*, Alejandra R. Alvarez3* and Silvana Zanlungo1*

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.

1Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile; 2Early Translation Branch, National Center for Advancing Translational Sciences (NCATS), NIH, Rockville, MD, United States; 3Laboratory of Cell Signaling, Center for Aging and Regeneration (CARE), Millennium Institute on Immunology and Immunotherapy (IMII), Department of Cellular and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago, Chile; 4Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States; 5School of Medical Technology, Health Sciences Faculty, Universidad San Sebastián, Santiago, Chile; 6Center for Genomics and Bioinformatics, Faculty of Science, Universidad Mayor, Santiago, Chile; 7Cell Communication and Migration Laboratory, Institute of Biochemistry and Molecular Cell Biology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 8Instituto de Medicina Molecular Joȧo Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

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