Sphingolipids in the Pathogenesis of Parkinson’s Disease and Parkinsonism

Lin, Guang; Wang, Liping; Marcogliese, Paul C.; Bellen, Hugo J.

doi:10.1016/j.tem.2018.11.003

Cited by 98 publications

(82 citation statements)

References 82 publications

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“…Alterations in sphingolipid lipid homeostasis are linked to lysosomal dysfunction and involved in PD pathogenesis [65,78,87]. Heterozygous mutations in GBA1 are associated with an increased risk for PD [30,99].…”

Section: Discussionmentioning

confidence: 99%

“…The knowledge acquired from the protein products of PD associated genes indicates that mitochondrial dysfunction, impaired intracellular trafficking, dysfunctional autophagylysosomal protein degradation pathways and α-synuclein aggregation are associated with neuronal death in PD [3,17,33,44,78,117]. Several PD associated genes regulate membrane dynamics wherein mutations cause lipid homeostasis alterations associated with lysosomal dysfunction [34,35,65]. In particular, mutations in GBA1 encoding the lysosomal enzyme glucocerebrosidase (GCase) increase the risk for PD with an estimated odds ratio of 5.4 [99].…”

Section: Introductionmentioning

confidence: 99%

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Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

et al. 2020

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Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synucleinpositive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.Keywords Parkinson's disease · Massive parallel sequencing · ATP10B P-type ATPase · Endo-lysosomal lipid flippase · Loss-of-function · Glucosylceramide Shaun Martin and Stefanie Smolders shared first authors and have contributed equally. Peter Vangheluwe and Christine Van Broeckhoven shared last and corresponding authors and have contributed equally.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

et al. 2020

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“…92 An additional central role has been proposed for ceramide metabolism in the pathobiology of PD based on retromer dysfunction and mitochondrial defects. 93 Together, these studies suggest that an imbalance of lipids may result in mitochondrial and endolysosomal dysfunction that leads to neuronal death in PD. Activating ceramidase, an enzyme that converts ceramide to sphingosine, would reduce ceramide levels and be potentially beneficial for treating CV disease, PD, insulin resistance, and inflammation.…”

Section: Glucose Lipid and Cholesterol Metabolismmentioning

confidence: 98%

“…Because the degradation of overproduced or pathological forms of α‐synuclein depends on sphingomyelinase, changes in ceramide abundance may play a central role in PD pathology . An additional central role has been proposed for ceramide metabolism in the pathobiology of PD based on retromer dysfunction and mitochondrial defects . Together, these studies suggest that an imbalance of lipids may result in mitochondrial and endolysosomal dysfunction that leads to neuronal death in PD.…”

Section: Contributions From the Basic Sciencesmentioning

confidence: 99%

Understanding the Links Between Cardiovascular Disease and Parkinson's Disease

et al. 2019

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Studies investigating the associations between genetic or environmental factors and Parkinson's disease (PD) have uncovered a number of factors shared with cardiovascular disease, either as risk factors or manifestations of cardiovascular disease itself. Older age, male sex, and possibly type 2 diabetes are examples. On the other hand, coffee consumption and physical activity are each associated with a lower risk of both PD and cardiovascular disease. This observation raises questions about the underlying pathophysiological links between cardiovascular disease and PD. There is evidence for common mechanisms in the areas of glucose metabolism, cellular stress, lipid metabolism, and inflammation. On the other hand, smoking and total/low‐density lipoprotein cholesterol appear to have opposite associations with cardiovascular disease and PD. Thus, it is uncertain whether the treatment of cardiovascular risk factors will impact on the onset or progression of PD. The available data suggest that a nuanced approach is necessary to manage risk factors such as cholesterol levels once the associations are better understood. Ultimately, the choice of therapy may be tailored to a patient's comorbidity profile. This review presents the epidemiological evidence for both concordant and discordant associations between cardiovascular disease and PD, discusses the cellular and metabolic processes that may underlie these links, and explores the implications this has for patient care and future research. © 2019 International Parkinson and Movement Disorder Society

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“…Smpd4 encoding for nSMase3 in ER and Golgi apparatus was found unchanged, while Smpd5 encoding for mitochondrial nSMase (MA-nSMase) was found upregulated in both tissues, reaching significance in cerebellum (cerebellum: 135%, p = 0.0454; spinal cord: 153%, p = 0.0940). This increase may be relevant for the generation of ceramides that trigger apoptosis via the mitochondrial pathway [103,114,115]. Further investigation of aSMase, nSMase1 and nSMase2 protein levels in cerebellum interestingly revealed a strong decrease in aSMase (47%, p < 0.0001) and no change for nSMase1 (93%, p = 0.1997) or nSMase2 (99%, p = 0.9933) levels, contrasting with the transcript data perhaps because of the limited sensitivity of Western blots for <2-fold changes or due to inadequate antibody quality ( Figure 4C).…”

Section: Enzymatic Production Of Ceramide In Atxn2-cag100-kin Mouse Nmentioning

confidence: 99%

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

Sen¹,

Arsovic²,

Meierhofer³

et al. 2019

Preprint

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Ataxin-2 (ATXN2) acts during stress-responses, modulating mRNA translation and nutrient metabolism. Atxn2 knockout mice exhibit progressive obesity, dyslipidemia and insulin resistance. Conversely, the progressive ATXN2 gain-of-function due to polyGlutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2), with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-KnockIn (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin and gangliosides GM1a/GD1b, despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides, with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, of Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very-long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage, not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals, so our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode and mouse orthologs as mTORC1 inhibitors and autophagy promoters.

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Sphingolipids in the Pathogenesis of Parkinson’s Disease and Parkinsonism

Cited by 98 publications

References 82 publications

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export

Understanding the Links Between Cardiovascular Disease and Parkinson's Disease

In Spino-Cerebellar Tissue, Ataxin-2 Expansion Affects Ceramide-Sphingomyelin Metabolism

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