Gaucher’s Disease Glucocerebrosidase and -synuclein form a bidirectional pathogenic loop in synucleinopathies

By Joseph R. Mazzulli, You-hai Xu, Ying Sun, Adam L. Knight, P. McLean, G. Caldwell, E. Sidransky, G. Grabowski, D. Krainc. Cell, 2011

1,296 citations recorded by the source corpus.

Summary Parkinson’s disease (PD), an adult neurodegenerative disorder, has been clinically linked to lysosomal storage disorder, Gaucher disease (GD), but the mechanistic connection has been unknown. 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 a-synuclein (a-syn), and results in neurotoxicity through aggregation dependent mechanisms. GlcCer, the GCase substrate, directly influenced amyloid formation of purified a-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that a-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 a-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.

Subfields: Cell Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/1ac42fba0493d08bab5930541c0f68568ebbd431

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In Cell Biology

1. P. Jenner
2. Leonidas Stefanis
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In Neurology

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Citations in the corpus

• Parkinson disease: from pathology to molecular disease mechanisms. (2013, background): “Indeed, GCase deficiency leads to a-synuclein accumulation both in vitro and in vivo [89,164].”
• A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments (2017, background): “Patients with GD1 have an increased risk of developing Parkinson’s disease (4–20 times greater), often at an earlier age than in normal PD [43,47,106,107].”
• α-Synuclein in Parkinson's disease. (2012, background): “According to some, loss-of-function of GBA is sufficient to induce a-synuclein accumulation and aggregation (Manning-Bog et al. 2010; Mazzulli et al. 2011; Xu et al. 2011), which may occur secondary to lysosomal dysfunction (Mazzulli et al.”
• Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. (2017, positive): “In PD patients without GBA mutations, the levels and activity of the enzyme are decreased in brain areas with increased α-syn levels in early disease stages (Mazzulli et al., 2011; Murphy et al., 2014).”
• Genetics of Parkinson's disease. (2012, background): “In turn, a-synuclein inhibits the lysososmal activity of b-glucocerebrosidase, as shown in neurons and idiopathic PD brain (Mazzulli et al. 2011).”
• 13 reasons why the brain is susceptible to oxidative stress (2018, neutral): “in PD pathogenesis [161]—and elevated mitochondrial [H2O2].”
• TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity (2013, background): “In humans, PD has been genetically linked to the rare lysosomal storage diseases, Gaucher disease and Sanfilippo syndrome (20, 21), and polymorphism in the lysosomal genes Lysosomal associated membrabe protein 2 (LAMP2) andAdenosine-3-phosphate 13A2 (ATP13A2) has recently been linked with PD (22, 23”