Reduced glucocerebrosidase is associated with increased a-synuclein in sporadic Parkinsonâs disease
Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are the most frequent known genetic risk factor for Parkinsonâs disease. Reduced glucocerebrosidase and a-synuclein accumulation are directly related in cell models of Parkinsonâs disease. We investigated relationships between Parkinsonâs disease-specific glucocerebrosidase deficits, glucocerebrosidase-related pathways, and a-synuclein levels in brain tissue from subjects with sporadic Parkinsonâs disease without GBA1 mutations. Brain regions with and without a Parkinsonâs disease-related increase in a-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinsonâs disease (n = 19) and age- and post-mortem delay-matched controls (n = 10). Levels of glucocerebrosidase, a-synuclein and related lysosomal and autophagic proteins were assessed by western blotting. Glucocerebrosidase enzyme activity was measured using a fluorimetric assay, and glucocerebrosidase and a-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 Parkinsonâs disease in regions with increased a-synuclein levels although limited inclusion formation, whereas GBA1 messenger RNA expression was non-selectively reduced in Parkinsonâs disease. The selective loss of lysosomal glucocerebrosidase was directly related to reduced lysosomal chaperone-mediated autophagy, increased a-synuclein and decreased ceramide. Glucocerebrosidase deficits in sporadic Parkinsonâs disease are related to the abnormal accumulation of a-synuclein and are associated with substantial alterations in lysosomal chaperone-mediated autophagy pathways and lipid metabolism. Our data suggest that the early selective Parkinsonâs 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 Parkinsonâs disease pathology.
|Authors||Murphy, K.E.; Gysbers, A.M.; Abbott, S.K.; Tayebi, N.; Woojin, S.K.; Sidransky, E.; Cooper, A.; Garner, B.; Halliday, G.|
|Published Date||2014-12-01 00:00:00|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/24477431|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12521|