CHARACTERIZATION AND RESCUE OF THE ALTERATIONS IN MOUSE AND HUMAN OLIGODENDROCYTES MODELING THE ACID SPHINGOMYELINASE DEFICIENCY

Acid Sphingomyelinase Deficiency (ASMD) is a lysosomal storage disorder (LSD) caused by mutations in the gene encoding the acid sphingomyelinase (ASM), leading to cellular accumulation of sphingomyelin (SM). The main pathological hallmarks of the fatal infantile neurovisceral form of ASMD include demyelination, microgliosis, and progressive neurodegeneration.
Myelination in the central nervous system relies on mature oligodendrocytes (OLs). Defects in myelin have been traditionally assigned a secondary pathological role in LSDs. However, recent studies from our laboratory pointed to demyelination as a triggering pathogenic factor for microgliosis and neurodegeneration in ASMD. Deciphering the causes of demyelination is thus important to understand and treat ASMD pathology.
We first used the mouse model for the disease, which lacks the ASM (ASMko). Our results showed impaired maturation of OLs in the cerebellum of ASMko mice where neurodegeneration is evident. Experiments performed in primary cultures from ASMko mice and differentiated from pluripotent human stem cells (iPSCs) lacking ASM also showed intrinsic defects in the morphological differentiation of ASMko OLs due to SM accumulation. To overcome ASMko OL alterations we used vitamin D3, which has been shown to facilitate OL differentiation and to enhance the Neutral Sphingomyelinase reducing SM levels. VitD3 treatment ameliorated OL differentiation defects in vitro. When administered in the diet, VitD3 prevented myelin and OL alterations and behaviour in ASMko mice.
These results, obtained in mouse and human models, contribute to understand brain pathology in ASMD and support a diet supplemented with VitD3 as a therapeutic strategy for this fatal disease.