Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease

Abstract

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in the GBA1 and LRRK2 genes. GBA1 mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic, GBA1-linked, or LRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and progression to dementia. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to progression to dementia.

Lysosomal storage, impaired autophagy and innate immunity in Gaucher and Parkinson's diseases: insights for drug discovery

“…Accordingly, circulating glucosylsphingosine (GlcSph) is elevated in GD and PD patients [ 60 ]. A recent study showed GlcSph levels are raised in multiple brain regions in both idiopathic and GBA1 -linked PD patients, demonstrating a positive correlation with αSyn pathology [ 61 ]. GlcSph is formed by deacylation of GlcCer by the lysosomal enzyme acid ceramidase and high levels of this sphingolipid have been identified in nGD brains.…”

Exosomes in the Diagnosis of Neuropsychiatric Diseases: A Review

“…In PD patients, aberrant protein aggregation is the main pathogenic mechanism [ 80 ]. Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to abnormal protein aggregation to form Lewy bodies [ 117 , 118 ], and the protein ratio of urinary exosome-phosphorylated LRRK2 (Ser(P)-129 LRRK2) to total LRRK2 is significantly increased in PD patients [ 119 ]. Plasma exosomal α-synuclein is increased in PD patients compared with healthy controls [ 8 ]; serum neuronal exosomal α-synuclein is significantly higher than in the APS group [ 9 ], and serum and plasma neuronal exosomal α-synuclein are significantly lower than in the multiple system atrophy (MSA) group [ 8 ].…”

AAV delivery ofGBA1suppresses α-synuclein accumulation in Parkinson’s disease models and restores motor dysfunction in a Gaucher’s disease model

“…The reduced GCase activity can be detected in the cerebrospinal fluid (CSF) and blood of GBA-PD patients [24][25][26], as well as in post mortem brain tissues [27]. In GBA-PD, GCase activity was the primary variable determining GlcSph levels which in turn shows a strong correlation with α-synuclein pathology in all brain areas other than the cerebellum, a brain region that does not exhibit PD pathology [27]. In vitro and in vivo models have been developed based on expression of pathogenic GBA1 mutants or administration of the GCase inhibitor conduritol β epoxide (CBE), to investigate the impact of reduced GCase levels on glycosphingolipid accumulation, lysosomal dysfunction, and increased α-synuclein aggregation [28,29].…”

“…Approximately 5-20% of PD patients carry a heterozygous GBA1 mutation (GBA-PD), differentiated by a 30-40% reduction in GCase activity, earlier disease onset including an increased risk for developing dementia with an up to five years earlier onset [12][13][14][15][16][17][18][19][20][21][22][23]. The reduced GCase activity can be detected in the cerebrospinal fluid (CSF) and blood of GBA-PD patients [24][25][26], as well as in post mortem brain tissues [27]. In GBA-PD, GCase activity was the primary variable determining GlcSph levels which in turn shows a strong correlation with α-synuclein pathology in all brain areas other than the cerebellum, a brain region that does not exhibit PD pathology [27].…”