C-ABL kinase in Niemann Pick type a disease : its implication in the pathogenic mechanisms leading to autophagic flux alterations and neurodegeneration.
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Date
2020
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Abstract
Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative and autosomal
recessive disorder. It is characterized by deficiency in acid sphingomyelinase (ASM) and
accumulation of sphingomyelin and cholesterol in lysosomes. Unfortunately, there is no
cure for patients who die between 2-3 years of age.
Previously we described that the c-Abl proapoptotic signaling pathway is key in neuronal
death in different neurodegenerative diseases, including lysosomal disorders.
Furthermore, recent studies show a role for c-Abl in autophagy and cellular clearance,
processes that depend on the lysosome, and are essential for keeping cellular
homeostasis. Indeed, autophagy dysfunctions are involved in different pathologies,
including neurodegenerative diseases. Considering these antecedents, we propose to
evaluate if c-Abl is hyperactivated and modulates autophagy and cellular clearance in NPA
disease.
The hypothesis of this thesis is that c-Abl hyperactivation blocks the autophagy flux
contributing to the neuronal pathogenesis in Niemann Pick type A disease. Our general
aim is to determine if c-Abl hyperactivation blocks the autophagy flux contributing to the
neuronal pathogenesis in Niemann Pick type A disease. The specific aims are: 1) To
determine if the c-Abl signaling pathway is hyperactivated and participates in NPA disease
neurodegeneration and 2) To evaluate if hyperactivation of the c-Abl signaling pathway
inhibits autophagy flux in NPA models. We used several NPA models including; fibroblasts
from NPA patients, Neural Stem Cells derived from these fibroblasts and a NPA mouse. In these models we modulated c-Abl activity and evaluated cell death, cerebellar
inflammation and autophagy flux.
Our results show that: i) c-Abl is hyperactivated and contributes to the
neurodegeneration in in vitro and in vivo NPA models; ii) There are lysosomal and
autophagy alterations in NPA models; iii) c-Abl inhibition induces autophagy and
decreases lipid accumulation in in vitro NPA models; iv) c-Abl inhibition decreases
neuronal death and inflammation at the cerebellum and improves locomotor function in
NPA mice and v) the downregulated genes in NPA fibroblasts increase their expression
upon Imatinib treatment. Interestingly, these genes are direct or indirectly related with
autophagy.
These results give new antecedents to understand the role of c-Abl in autophagy
regulation and its contribution to the NPA disease pathogenic mechanisms. Additionally,
these results allow us to propose c-Abl inhibitors as a therapeutic option for this disease.
Description
Tesis (Doctor en Ciencias Médicas)--Pontificia Universidad Católica de Chile, 2020