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

Research output: Contribution to journalArticle

588 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)37-52
Number of pages16
JournalCell
Volume146
Issue number1
DOIs
StatePublished - Jul 8 2011

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Synucleins
Glucosylceramidase
Gaucher Disease
Parkinson Disease
Neurons
Glucosylceramides
Lysosomes
Amyloid
Neurodegenerative Diseases
Proteolysis
Brain
Agglomeration
Feedback
Degradation
Substrates

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mazzulli, Joseph R. ; Xu, You Hai ; Sun, Ying ; Knight, Adam L. ; McLean, Pamela J. ; Caldwell, Guy A. ; Sidransky, Ellen ; Grabowski, Gregory A. ; Krainc, Dimitri. / Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. In: Cell. 2011 ; Vol. 146, No. 1. pp. 37-52.
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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.",
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Mazzulli, JR, Xu, YH, Sun, Y, Knight, AL, McLean, PJ, Caldwell, GA, Sidransky, E, Grabowski, GA & Krainc, D 2011, 'Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies', Cell, vol. 146, no. 1, pp. 37-52. https://doi.org/10.1016/j.cell.2011.06.001

Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. / Mazzulli, Joseph R.; Xu, You Hai; Sun, Ying; Knight, Adam L.; McLean, Pamela J.; Caldwell, Guy A.; Sidransky, Ellen; Grabowski, Gregory A.; Krainc, Dimitri.

In: Cell, Vol. 146, No. 1, 08.07.2011, p. 37-52.

Research output: Contribution to journalArticle

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AU - Knight, Adam L.

AU - McLean, Pamela J.

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AU - Sidransky, Ellen

AU - Grabowski, Gregory A.

AU - Krainc, Dimitri

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