Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies

Joseph R. Mazzulli; You Hai Xu; Ying Sun; Adam L. Knight; Pamela J. McLean; Guy A. Caldwell; Ellen Sidransky; Gregory A. Grabowski; Dimitri Krainc

doi:10.1016/j.cell.2011.06.001

Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies

Joseph R. Mazzulli, You Hai Xu, Ying Sun, Adam L. Knight, Pamela J. McLean, Guy A. Caldwell, Ellen Sidransky, Gregory A. Grabowski, Dimitri Krainc^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

1107 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	37-52
Number of pages	16
Journal	Cell
Volume	146
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2011.06.001
State	Published - Jul 8 2011

Funding

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.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2011.06.001

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@article{f3c259ffebc745169a00ab1802c82b30,

title = "Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies",

abstract = "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.",

author = "Mazzulli, {Joseph R.} and Xu, {You Hai} and Ying Sun and Knight, {Adam L.} and McLean, {Pamela J.} and Caldwell, {Guy A.} and Ellen Sidransky and Grabowski, {Gregory A.} and Dimitri Krainc",

note = "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.). ",

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doi = "10.1016/j.cell.2011.06.001",

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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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Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies

Abstract

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