Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of mouse brain

Aging is the biggest risk factor for Parkinson’s disease (PD). The majority of PD cases are non-familial, and the connection between aging and PD-associated genes is not well understood. Haploinsufficiency in GBA, leading to a reduction in glucocerebrosidase (GCase) activity, is one of the most common genetic risk factors for PD. Furthermore, GCase activity is also reduced in brain regions of sporadic PD patients, with a corresponding accumulation of its glycosphingolipid (GSL) substrates. Recent findings in PD patients and aging control cases, and in human PD patient iPSC neurons, have shown an age-dependent reduction in GCase activity and an elevation of some GSLs. We therefore asked whether aging-induced changes to lysosomal GCase activity and GSL homeostasis in the brain could also be reflected in other non-human mammalian systems. Increases in brain polyubiquitin and the lysosomal-associated membrane protein, LAMP2A, were found in 24-month old wildtype mice compared to 1.5-month old mice. A lipidomic analysis was performed on brains of wildtype mice of different strains between 1.5 and 24 months of age. Aging created GSL changes that are reminiscent of sporadic Parkinson’s disease. Levels of glucosylceramide, glucosylsphingosine, lactosylceramide and GM1a were elevated in the brain of aged mice, and levels of complex gangliosides, GD1a, GD1b and GT1b, were reduced with age. Parallel biochemical analyses revealed a change in lipid metabolism probably mediated by lysosomal hydrolases, with reduced GCase and increased neuraminidase activity. Based on these data we hypothesize that perturbation of GSL metabolism in the aging brain may precede or be part of abnormal protein handling, and may accelerate PD pathophysiological processes in vulnerable neurons in PD and other age-related neurodegenerative disorders