Neural precursor cell cultures from GM2 gangliosidosis animal models recapitulate the biochemical and molecular hallmarks of the brain pathology.
In this work we showed that genotype-related patterns of hexosaminidase activity, isoenzyme composition, gene expression and ganglioside metabolism observed during embryonic and postnatal brain development are recapitulated during the progressive stages of neural precursor cell (NPC) differentiation to mature glia and neurons in vitro. Further, by comparing NPCs and their differentiated progeny established from Tay-Sachs (TS) and Sandhoff (SD) animal models with the wild-type counterparts, we studied the events linking the accumulation of undegraded substrates to hexosaminidase activity. We showed that similarly to what observed in brain tissues in TS NPCs and progeny, the stored GM2 was partially converted by sialidase to GA2, which can be then degraded in the lysosomes to its components. The latter can be used in a salvage pathway for the formation of GM3. Interestingly, results obtained from ganglioside feeding assays and from measurement of lysosomal sialidase activity suggest that a similar pathway might work also in the SD model.
Martino
Sabata
S
Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Sezione di Biochimica e Biologia Molecolare, Università di Perugia, Perugia, Italy.
di Girolamo
Ilaria
I
Cavazzin
Chiara
C
Tiribuzi
Roberto
R
Galli
Rossella
R
Rivaroli
Anna
A
Valsecchi
Manuela
M
Sandhoff
Konrad
K
Sonnino
Sandro
S
Vescovi
Angelo
A
Gritti
Angela
A
Orlacchio
Aldo
A
D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020143:Gangliosidoses, GM2 / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008818:Mice, Neurologic Mutants; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers