Reduced glucocerebrosidase is associated with increased α-synuclein in sporadic Parkinson’s disease

Abstract

Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are the most frequent known genetic risk factor for Parkinson's disease. Reduced glucocerebrosidase and α-synuclein accumulation are directly related in cell models of Parkinson's disease. We investigated relationships between Parkinson's disease-specific glucocerebrosidase deficits, glucocerebrosidase-related pathways, and α-synuclein levels in brain tissue from subjects with sporadic Parkinson's disease without GBA1 mutations. Brain regions with and without a Parkinson's disease-related increase in α-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinson's disease (n = 19) and age- and post-mortem delay-matched controls (n = 10). Levels of glucocerebrosidase, α-synuclein and related lysosomal and autophagic proteins were assessed by western blotting. Glucocerebrosidase enzyme activity was measured using a fluorimetric assay, and glucocerebrosidase and α-synuclein messenger RNA expression determined by quantitative polymerase chain reaction. Related sphingolipids were analysed by mass spectrometry. Multivariate statistical analyses were performed to identify differences between disease groups and regions, with non-parametric correlations used to identify relationships between variables. Glucocerebrosidase protein levels and enzyme activity were selectively reduced in the early stages of Parkinson's disease in regions with increased α-synuclein levels although limited inclusion formation, whereas GBA1 messenger RNA expression was non-selectively reduced in Parkinson's disease. The selective loss of lysosomal glucocerebrosidase was directly related to reduced lysosomal chaperone-mediated autophagy, increased α-synuclein and decreased ceramide. Glucocerebrosidase deficits in sporadic Parkinson's disease are related to the abnormal accumulation of α-synuclein and are associated with substantial alterations in lysosomal chaperone-mediated autophagy pathways and lipid metabolism. Our data suggest that the early selective Parkinson's disease changes are likely a result of the redistribution of cellular membrane proteins leading to a chronic reduction in lysosome function in brain regions vulnerable to Parkinson's disease pathology.

LRRK2 deficiency impacts ceramide metabolism in brain

“…Moreover, more needs to be done to understand if LRRK2 directly or indirectly regulates Cer metabolism through other pathways. Our results together with other recently published papers [2,5,7,11,27,33] suggest that PD shares several features with sphingolipid disorders, opening new avenues for the identification of novel therapeutic strategies.…”

“…To achieve this, we performed targeted LC-MS measurements and focused on sphingolipids, whose alterations in brain tissue of PD patients have been previously reported [5] and have been associated with dysregulation in GBA1 level and activity [33].…”

“…On the other hand, in idiopathic PD patients as well as in PD patients carrying GBA1 mutations and in GD patients, a decrease in GBA1 level is usually associated with a decrease in GBA1 activity [27,33,[35][36][37][38][39][40] (Table 1). The overall picture that emerges from this analysis is that Cer metabolism is important in PD etiopathogenesis.…”

Impairment of chaperone-mediated autophagy induces dopaminergic neurodegeneration in rats

“…It should be noted, however, that with the strategy utilized in the current study, LAMP2A deficiency resulted in a severe loss of nigral neurons, whereas, in the same LAMP2A-deficient animals, other TH-negative but GFP-positive neurons along the needle tract were spared (data not shown), suggesting that dopaminergic neurons may be more vulnerable to CMA dysfunction compared to other neuronal cells. This may provide at least a partial explanation for the fact that, even though SNCA accumulates in various brain regions in PD, correlating inversely with decreased protein levels of LAMP2A and HSPA8/ HSC70, 21,22,23 pronounced neurodegeneration occurs predominantly within nigral dopaminergic neurons. As aging is the main risk factor associated with PD and other neurodegenerative disorders, it would be very important to investigate whether CMA dysfunction, manifested by decreased LAMP2A and/or HSPA8/HSC70 levels, also occurs in the human brain with aging and whether brain areas affected in PD such as the nigra, show lower LAMP2A and/or HSPA8/HSC70 levels during aging compared to other regions (e.g., the cerebellum) that are spared; however, such an analysis has not yet been performed.…”

“…19,20 In the context of PD, decreased LAMP2A [21][22][23] and HSPA8/ HSC70 21 protein levels are detected in human post-mortem PD brains, which-given that age is the primary risk factor for disease development 24 -renders LAMP2A abundance a valid target for both disease pathogenesis and therapy. We have previously shown that RNA-interference targeting LAMP2A results in significant accumulation of SNCA in cultured neurons, 17 whereas overexpression of LAMP2A in cell culture models and in dopaminergic neurons of the substantia nigra pars compacta (SNpc) is able to fully rescue neurotoxicity associated with elevated SNCA protein burden.…”