Autophagic impairment was identified in many
lysosomal storage diseases and adult
neurodegenerative diseases. It seems that this defect could be directly related to the appearance of a neurodegenerative phenotype and could contribute to worsen metabolite accumulation and lysosomal distress. Thus, autophagy is becoming a promising target for supportive
therapies. Autophagy alterations were recently identified also in
Krabbe disease.
Krabbe disease is characterized by extensive
demyelination and dysmyelination and it is due to the genetic loss of function of the lysosomal
enzyme galactocerebrosidase (GALC). This
enzyme leads to the accumulation of
galactosylceramide,
psychosine, and secondary substrates such as
lactosylceramide. In this paper, we induced autophagy through
starvation and examined the cellular response occurring in fibroblasts isolated from patients. We demonstrated that the inhibitory AKT-mediated phosphorylation of
beclin-1 and the BCL2-beclin-1 complex concur to reduce autophagosomes formation in response to
starvation. These events were not dependent on the accumulation of
psychosine, which was previously identified as a possible player in autophagic impairment in
Krabbe disease. We believe that these data could better elucidate the capability of response to autophagic stimuli in
Krabbe disease, in order to identify possible molecules able to stimulate the process.