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

Abstract

Aging is the predominant risk factor for both genetic and sporadic Parkinson’s disease (PD). The majority of PD cases are nonfamilial, and the connection between aging and PD-associated genes is not well understood. Haploinsufficiency of the GBA gene, 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 induced pluripotent stem cell neurons, have shown an age-dependent reduction in GCase activity and an elevation of some GSLs. We therefore asked whether aging-induced changes to both lysosomal and nonlysosomal GCase activity and GSL homeostasis in the brain could also be reflected in other nonhuman mammalian systems. Increases in brain polyubiquitin and the lysosomal-associated membrane protein, LAMP2A, were found in 24-month-old wild-type mice compared to 1.5-month-old mice. A lipidomic analysis was performed on brains of wild-type mice of different strains between 1.5 and 24 months of age. Aging created GSL changes that are reminiscent of sporadic PD. 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 may be part of abnormal protein handling and may accelerate PD pathophysiological processes in vulnerable neurons in PD and other age-related neurodegenerative disorders.

Role of the endolysosomal system in Parkinson’s disease

“…Cognitive areas such as hippocampus, frontal cortex, and amygdala also showed relative decrease in Gcase1 activity, along with a significant elevation of hippocampal glucosylsphingosine in sporadic cases (Gegg et al ). This correlates with a higher Lewy body burden identified in the hippocampus and medial temporal regions, as well as in a diffused cortical Lewy body pathology in GBA ‐linked PD (Watson and Leverenz ; Hallett et al ). These pathological observations strengthen clinical findings that cognitive deterioration is severe in PD patients with GBA mutations compared to that of sporadic cases (Liu et al ; Mata et al ).…”

Glucocerebrosidase: Functions in and Beyond the Lysosome

“…In line with these observations is the occurrence of hemolysis, multinucleated macrophages, neuropathology, growth retardation, and chronic low-grade inflammation in GD patients [4]. Of note, in the brain of ageing mice reduction of active GCase in combination with increased glucosylceramide and glucosylsphingosine levels were observed [116].…”

“…Of note, active GCase activity is also decreased, and corresponding glycosphingolipid substrate levels elevated, in the brain in PD without GBA1 mutations [114,115]. Abnormalities in multiple enzymes and other proteins involved in sphingolipid metabolism were observed in association with PD [114,116,117]. With increasing age, the brain of mice shows reduced GCase levels and increased amounts of lipid substrate [115].…”

Neurological effects of glucocerebrosidase gene mutations

“…These findings are within the broader context of an established literature implicating diminished mechanisms of cellular autophagy in idiopathic PD [66][67][68]. Interestingly, there appears to be an age-dependent reduction in GCase activity in both mice and human brain [69,70]. Moreover, GCase activity levels are reduced compared to controls in the brains of non-GBA idiopathic PD subjects [71]; however, studies looking at substrate accumulation are somewhat varied.…”