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

Abstract

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.

The c-Abl/p73 pathway induces neurodegeneration in a Parkinson's disease model

“…Moreover, it is necessary to determine the possible impact of this pharmacological treatment on PD progression, considering motor dysfunction, dopaminergic neuronal loss, and α-syn accumulation. Therefore, our data and previous findings strongly suggest using c-Abl inhibitors with high brain penetrances such as Imatinib and Neurotinib ( Marín et al, 2022 ) to reduce the main hallmarks of PD.…”

Nanoreporter Identifies Lysosomal Storage Disease Lipid Accumulation Intracranially

“…We validated the reporter in a neuronal pharmacological cellular model, SH-SY5Y cells treated with an ASM inhibitor desipramine [10 μM]. 48,49 We confirmed the NPA phenotype differential accumulation of C11-SM (Figure 2A,B). Upon incubation of the lipid reporter, local intracellular internalization was observed (Figure 2C).…”

“…Recent papers found that ASM deficiency is accompanied by autophagy lysosomal alterations. , A recent study found that c-Abl tyrosine kinase is activated in NPA models and downregulates autophagy, including in SH-SY5Y cells treated with desipramine . Moreover, the authors found that treatment with imatinib, a clinical c-Abl inhibitor, restores autophagy flux (Figure S3) and lowers sphingomyelin accumulation in NPA cell models.…”

Neuronopathic Gaucher disease: Beyond lysosomal dysfunction

“…Moreover, the c-Abl pharmacological inhibition in NPC models reduced cerebellar apoptosis and promoted autophagy and cholesterol clearance—changes associated with increased TFEB nuclear localization, TFEB target gene expression, lysosomal biogenesis, and exocytosis (Contreras et al, 2020 ). Recently, we found that the inhibition of c-Abl is also involved in alterations in the autophagy lysosomal pathway in Niemann–Pick A (NPA), a disease in which sphingomyelin accumulates in lysosomes (Marín et al, 2022 ). The inhibition of c-Abl improves autophagy lysosomal function, restoring autophagy flux and sphingomyelin accumulation in NPA models (Marín et al, 2022 ).…”

“…Recently, we found that the inhibition of c-Abl is also involved in alterations in the autophagy lysosomal pathway in Niemann–Pick A (NPA), a disease in which sphingomyelin accumulates in lysosomes (Marín et al, 2022 ). The inhibition of c-Abl improves autophagy lysosomal function, restoring autophagy flux and sphingomyelin accumulation in NPA models (Marín et al, 2022 ). These results show that alterations in c-Abl signaling are relevant in LSDs and suggest that it could also play an essential pathogenic role in GD.…”