TY - JOUR
T1 - Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies
AU - Mazzulli, Joseph R.
AU - Xu, You Hai
AU - Sun, Ying
AU - Knight, Adam L.
AU - McLean, Pamela J.
AU - Caldwell, Guy A.
AU - Sidransky, Ellen
AU - Grabowski, Gregory A.
AU - Krainc, Dimitri
N1 - Funding Information:
We thank Harry Ischiropoulos for pCDNA3.1 human α-syn plasmids and syn303 antibody, Benoit I. Giasson for the SNL-1 antibody, and Kimberly Kegel for technical advice on liposome formation. This work was supported by National Institutes of Health grants R01NS051303 (D.K.) and F32NS066730 (J.R.M.) from the National Institute of Neurological Disorders and Stroke, R01DK36729 (G.A.G.), and the Intramural Programs of the National Human Genome Research Institute and the National Institutes of Health (E.S.).
PY - 2011/7/8
Y1 - 2011/7/8
N2 - Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
AB - Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
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U2 - 10.1016/j.cell.2011.06.001
DO - 10.1016/j.cell.2011.06.001
M3 - Article
C2 - 21700325
AN - SCOPUS:79960009804
SN - 0092-8674
VL - 146
SP - 37
EP - 52
JO - Cell
JF - Cell
IS - 1
ER -