The interplay between Glucocerebrosidase, α-synuclein and lipids in human models of Parkinson’s disease

Muñoz, Sonia Sanz; Petersen, Daniel; Marlet, Frederik Ravnkilde; Kücükköse, Ebru; Galvagnion, Céline

doi:10.1016/j.bpc.2020.106534

Cited by 39 publications

(27 citation statements)

References 152 publications

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“…The rate of neurodegeneration is accelerated in GBA mutation carriers compared with sporadic PD ( 38 ), and thus it would be reasonable to expect LFP signal asymmetry in GBA mutation carriers as demonstrated in the present study. As mutations in the GCase enzyme result in accumulation of sphingolipids and subsequent alpha-synuclein accumulation ( 39 ), the process by which this translates to changes in beta is unknown.…”

Section: Discussionmentioning

confidence: 99%

Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study

et al. 2021

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Introduction: Up to 27% of individuals undergoing subthalamic nucleus deep brain stimulation (STN-DBS) have a genetic form of Parkinson's disease (PD). Glucocerebrosidase (GBA) mutation carriers, compared to sporadic PD, present with a more aggressive disease, less asymmetry, and fare worse on cognitive outcomes with STN-DBS. Evaluating STN intra-operative local field potentials provide the opportunity to assess and compare symmetry between GBA and non-GBA mutation carriers with PD; thus, providing insight into genotype and STN physiology, and eligibility for and programming of STN-DBS. The purpose of this pilot study was to test differences in left and right STN resting state beta power in non-GBA and GBA mutation carriers with PD.Materials and Methods: STN (left and right) resting state local field potentials were recorded intraoperatively from 4 GBA and 5 non-GBA patients with PD while off medication. Peak beta power expressed as a ratio to total beta power (peak beta ratio) was compared between STN hemispheres and groups while co-varying for age, age of disease onset, and disease severity.Results: Peak beta ratio was significantly different between the left and the right STN for the GBA group (p < 0.01) but not the non-GBA group (p = 0.56) after co-varying for age, age of disease onset, and disease severity.Discussion: Peak beta ratio in GBA mutation carriers was more asymmetric compared with non-mutation carriers and this corresponded with the degree of clinical asymmetry as measured by rating scales. This finding suggests that GBA mutation carriers have a physiologic signature that is distinct from that found in sporadic PD.

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Section: Discussionmentioning

confidence: 99%

Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study

et al. 2021

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“…PD patients with GBA mutations have an earlier disease onset and a higher risk of dementia [ 118 ], and latest study has revealed that GBA activity is negatively correlated with level of α-synuclein [ 119 ]. PD patients have significantly higher α-synuclein levels with lower GBA activity in peripheral blood mononuclear cells [ 120 ].…”

Section: Intestinal Dysfunctions In Pdmentioning

confidence: 99%

Intestinal Inflammation and Parkinson’s Disease

Li¹,

Chen²,

Jiang³

et al. 2021

Aging and disease

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“…In particular, several genome wide association studies have identified genes regulating lipid metabolism as PD risk factors [ 34 ]. Also, mutations of glucocerebrosidase (GCase) gene, associated with a decrease in GCase activity, is leading to the accumulation of both glucosylceramide and αSyn and is the highest risk factor of developing PD [ 35 ]. In a Drosophila model carrying a GCase mutation and expressing human αSyn, it was proposed that the binding of lipids to αSyn contributes to its pathogenic conversion [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson’s disease

et al. 2021

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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αSyn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human αSyn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins Perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/midway, fatty acid transport protein/dFatp) and catabolic (brummer TG lipase) enzymes, indicating that alternative mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, which localized to LDs in both Drosophila photoreceptor neurons and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of αSyn to proteolytic digestion, a characteristic of αSyn aggregation in human neurons. We propose that αSyn cooperates with LD proteins to inhibit lipolysis and that binding of αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn in neurons.

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The interplay between Glucocerebrosidase, α-synuclein and lipids in human models of Parkinson’s disease

Cited by 39 publications

References 152 publications

Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study

Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study

Intestinal Inflammation and Parkinson’s Disease

Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson’s disease

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