# c-Abl/TFEB Pathway Activation as a Common Pathogenic Mechanism in Lysosomal Storage Diseases: Therapeutic Potential of c-Abl Inhibitors

## TL;DR

This study shows that c-Abl/TFEB pathway activation is a shared problem in several lysosomal storage diseases and suggests c-Abl inhibitors could be a new treatment option.

## Contribution

The study identifies c-Abl/TFEB pathway activation as a common pathogenic mechanism in LSDs and evaluates c-Abl inhibitors as potential therapies.

## Key findings

- c-Abl activation (p-c-Abl) is a common pathogenic mechanism in Gaucher, NPA, and NPC diseases.
- c-Abl inhibitors and α-Tocopherol promote TFEB nuclear translocation and reduce cholesterol accumulation in LSD models.
- Treatment with c-Abl inhibitors enhances lysosomal clearance in neuronal and HeLa cell models of LSDs.

## Abstract

Lysosomal storage diseases (LSDs) are characterized by the accumulation of undegraded substrates within lysosomes, often associated with oxidative stress and impaired lysosomal function. In this study, we investigate the role of the c-Abl/TFEB pathway in different LSDs: Gaucher, Niemann-Pick type A (NPA), and Niemann-Pick type C (NPC). Our findings identify c-Abl activation (p-c-Abl) as a common pathogenic mechanism in these disorders. We demonstrate that c-Abl phosphorylates TFEB at Tyr173, leading to its cytoplasmic retention. Using pharmacological models of Gaucher, NPA and NPC in SH-SY5Y neuronal cells and HeLa cells, we assess the effects of the c-Abl inhibitors Imatinib and Neurotinib, as well as the antioxidant α-Tocopherol (α-TOH), on TFEB nuclear translocation and p-c-Abl protein levels. Additionally, we explore the effects of c-Abl inhibitors in cholesterol accumulation in LSDs neuronal models. Our results show that treatment with c-Abl inhibitors or α-TOH promotes TFEB nuclear translocation, enhances lysosomal clearance, and reduces cholesterol accumulation in all three LSD models. These findings highlight the c-Abl/TFEB pathway as a potential therapeutic target for LSDs and potentially other neurodegenerative disorders associated with lysosomal dysfunction.