Tay-Sachs CSF N-Glycan Profile by MALDI MS Reveals Incomplete Glycosylation

Tay Sachs disease (TSD) is a rare, heterogeneous, autosomal recessive disease caused by deficiency of the lysosomal enzyme hexosaminidase A (HexA) which degrades GM2 ganglioside. This degenerative neurological disease is one of a group of disorders called the GM2 gangliosidoses, themselves part of a larger group of lysosomal storage disorders. Most lysosomal enzymes are glycoproteins synthesized in the endoplasmic reticulum (ER), transported to the Golgi apparatus (GA) and targeted to lysosomes by proper glycosylation including acquisition of mannose-6-phosphate residue. Glycosylation affects several biological processes including signaling, adhesion, development and immune system functioning. Glycan structures regulate protein binding, targeting, folding, stability, activity and specificity. Glycan biosynthesis is not under direct genetic control, is not template driven and depends on the action of several glyco-enzymes: this is why glycosylation changes with cell types and disease conditions. Cerebrospinal fluid (CSF) N-glycome profile is aimed to analyze N-glycan structures of secreted glycoproteins including intrathecal synthesized glycoproteins. Thus, it allows to monitor disease-related glycosylation changes in the central nervous system. The aim of this study was to analyze the cerebral spinal fluid N-glycan profile of patients affected by TSD using MALDI mass spectrometry. We found differences in the CSF glycome between a patient with TSD and age and sex matched controls subjects. On the other hand, no differences were detected in serum N-glycan profiles. As TSD is a neurodegenerative disorder we wonder if it is possible to understand disease's mechanisms exploring the CSF N-glycome. There are currently no therapies for the treatment of TSD patients: glycomic analysis of CSF of patients with TSD may shed light on the pathophysiology of the disease and could be helpful to monitor the effectiveness of therapies based on enzyme replacement or substrate synthesis inhibition.