scholarly journals The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

2019 ◽  
Vol 20 (13) ◽  
pp. 3304 ◽  
Author(s):  
Rossella Indellicato ◽  
Marco Trinchera
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gaucher Disease ◽  
Lysosomal Storage Diseases ◽  
Krabbe Disease ◽  
Sphingolipid Metabolism ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Inborn Errors ◽  
Vesicle Traffic

Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.

scholarly journals Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson’s disease cohort

2019 ◽  
Author(s):  
O.E.E. Graham ◽  
T.L. Pitcher ◽  
Y. Liau ◽  
A.L. Miller ◽  
J.C. Dalrymple-Alford ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
New Zealand ◽  
Gaucher Disease ◽  
Nanopore Sequencing ◽  
Lysosomal Storage ◽  
Coding Region ◽  
Structural Variations ◽  
Sequencing Platform ◽  
Nanopore Dna Sequencing

AbstractIntroductionBi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson’s disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD.MethodWe examined amplicons encompassing the coding region of GBA (8.9kb) from 229 PD cases and 50 healthy controls using the GridION nanopore sequencing platform, and Sanger validation.ResultsWe detected 23 variants in 21 PD cases (9.2% of patients). We detected modest PD risk variant p.N409S (rs76763715) in one case, p.E365K (rs2230288) in 12 cases, and p.T408M (rs75548401) in seven cases, one of whom also had p.E365K. We additionally detected the possible risk variants p.R78C (rs146774384) in one case, p.D179H (rs147138516) in one case which occurred on the same haplotype as p.E365K, and one novel variant c.335C>T or p.(L335=), that potentially impacts splicing of GBA transcripts. Additionally, we found a higher prevalence of dementia among patients with GBA variants.ConclusionThis work confirmed the utility of nanopore sequencing as a high-throughput method to identify known and novel GBA variants, and to assign precise haplotypes. Our observations may contribute to improved understanding of the effects of variants on disease pathogenesis, and to the development of more targeted treatments.

scholarly journals Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

2020 ◽  
Vol 9 (2) ◽  
pp. 594 ◽  
Author(s):  
Silvia Paciotti ◽  
Elisabetta Albi ◽  
Lucilla Parnetti ◽  
Tommaso Beccari
Keyword(s):  
Parkinson’S Disease ◽  
Central Nervous System ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Gaucher Disease ◽  
Genetic Diseases ◽  
Sandhoff Disease ◽  
Krabbe Disease ◽  
Bioactive Lipids ◽  
Niemann Pick

Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson’s disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded α-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson’s disease.

scholarly journals Cell-autonomous expression of the acid hydrolase galactocerebrosidase

2020 ◽  
Vol 117 (16) ◽  
pp. 9032-9041
Author(s):  
Christina R. Mikulka ◽  
Joshua T. Dearborn ◽  
Bruno A. Benitez ◽  
Amy Strickland ◽  
Lin Liu ◽  
...  
Keyword(s):  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Krabbe Disease ◽  
Specific Cell ◽  
Acid Hydrolase ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Soluble Acid ◽  
Enzyme Deficient

Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as “cross-correction.” Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GALCLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease.

Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond

2011 ◽  
Vol 26 (9) ◽  
pp. 1593-1604 ◽  
Author(s):  
Tamar Shachar ◽  
Christophe Lo Bianco ◽  
Alessandra Recchia ◽  
Christoph Wiessner ◽  
Annick Raas-Rothschild ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gaucher Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Storage Disorders

scholarly journals Glycosphingolipid metabolism and its role in ageing and Parkinson’s disease

2021 ◽  
Author(s):  
Kerri-Lee Wallom ◽  
María E. Fernández-Suárez ◽  
David A. Priestman ◽  
Danielle te Vruchte ◽  
Mylene Huebecker ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lysosomal Storage Disorders ◽  
Sphingolipid Metabolism ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Acid Hydrolases ◽  
Catabolic Genes ◽  
Normal Ageing ◽  
Storage Disorders

AbstractIt is well established that lysosomal glucocerebrosidase gene (GBA) variants are a risk factor for Parkinson’s disease (PD), with increasing evidence suggesting a loss of function mechanism. One question raised by this genetic association is whether variants of genes involved in other aspects of sphingolipid metabolism are also associated with PD. Recent studies in sporadic PD have identified variants in multiple genes linked to diseases of glycosphingolipid (GSL) metabolism to be associated with PD. GSL biosynthesis is a complex pathway involving the coordinated action of multiple enzymes in the Golgi apparatus. GSL catabolism takes place in the lysosome and is dependent on the action of multiple acid hydrolases specific for certain substrates and glycan linkages. The finding that variants in multiple GSL catabolic genes are over-represented in PD in a heterozygous state highlights the importance of GSLs in the healthy brain and how lipid imbalances and lysosomal dysfunction are associated with normal ageing and neurodegenerative diseases. In this article we will explore the link between lysosomal storage disorders and PD, the GSL changes seen in both normal ageing, lysosomal storage disorders (LSDs) and PD and the mechanisms by which these changes can affect neurodegeneration.

scholarly journals The Emerging Role of the Lysosome in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2399
Author(s):  
Alba Navarro-Romero ◽  
Marta Montpeyó ◽  
Marta Martinez-Vicente
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Lysosomal Storage Diseases ◽  
Genetic Risk Factors ◽  
Brain Regions ◽  
Lysosomal Storage ◽  
Lysosomal Function ◽  
Lysosomal Dysfunction

Lysosomal function has a central role in maintaining neuronal homeostasis, and, accordingly, lysosomal dysfunction has been linked to neurodegeneration and particularly to Parkinson’s disease (PD). Lysosomes are the converging step where the substrates delivered by autophagy and endocytosis are degraded in order to recycle their primary components to rebuild new macromolecules. Genetic studies have revealed the important link between the lysosomal function and PD; several of the autosomal dominant and recessive genes associated with PD as well as several genetic risk factors encode for lysosomal, autophagic, and endosomal proteins. Mutations in these PD-associated genes can cause lysosomal dysfunction, and since α-synuclein degradation is mostly lysosomal-dependent, among other consequences, lysosomal impairment can affect α-synuclein turnover, contributing to increase its intracellular levels and therefore promoting its accumulation and aggregation. Recent studies have also highlighted the bidirectional link between Parkinson’s disease and lysosomal storage diseases (LSD); evidence includes the presence of α-synuclein inclusions in the brain regions of patients with LSD and the identification of several lysosomal genes involved in LSD as genetic risk factors to develop PD.

scholarly journals Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson’s disease

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Mylene Huebecker ◽  
Elizabeth B. Moloney ◽  
Aarnoud C. van der Spoel ◽  
David A. Priestman ◽  
Ole Isacson ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Strong Predictor ◽  
Brain Regions ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Genetic Risks ◽  
Normal Phase Hplc ◽  
First Time

Abstract Background Haploinsufficiency in the Gaucher disease GBA gene, which encodes the lysosomal glucocerebrosidase GBA, and ageing represent major risk factors for developing Parkinson’s disease (PD). Recently, more than fifty other lysosomal storage disorder gene variants have been identified in PD, implicating lysosomal dysfunction more broadly as a key risk factor for PD. Despite the evidence of multiple lysosomal genetic risks, it remains unclear how sphingolipid hydrolase activities, other than GBA, are altered with ageing or in PD. Moreover, it is not fully known if levels of glycosphingolipid substrates for these enzymes change in vulnerable brain regions of PD. Finally, little is known about the levels of complex gangliosides in substantia nigra which may play a significant role in ageing and PD. Methods To study sphingolipid hydrolase activities and glycosphingolipid expression in ageing and in PD, two independent cohorts of human substantia nigra tissues were obtained. Fluorescent 4-methylumbelliferone assays were used to determine multiple enzyme activities. The lysosomal GBA and non-lysosomal GBA2 activities were distinguished using the inhibitor NB-DGJ. Sensitive and quantitative normal-phase HPLC was performed to study glycosphingolipid levels. In addition, glycosphingolipid levels in cerebrospinal fluid and serum were analysed as possible biomarkers for PD. Results The present study demonstrates, in two independent cohorts of human post-mortem substantia nigra, that sporadic PD is associated with deficiencies in multiple lysosomal hydrolases (e.g. α-galactosidase and β-hexosaminidase), in addition to reduced GBA and GBA2 activities and concomitant glycosphingolipid substrate accumulation. Furthermore, the data show significant reductions in levels of complex gangliosides (e.g. GM1a) in substantia nigra, CSF and serum in ageing, PD, and REM sleep behaviour disorder, which is a strong predictor of PD. Conclusions These findings conclusively demonstrate reductions in GBA activity in the parkinsonian midbrain, and for the first time, reductions in the activity of several other sphingolipid hydrolases. Furthermore, significant reductions were seen in complex gangliosides in PD and ageing. The diminished activities of these lysosomal hydrolases, the glycosphingolipid substrate accumulation, and the reduced levels of complex gangliosides are likely major contributors to the primary development of the pathology seen in PD and related disorders with age.

scholarly journals Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

2021 ◽  
Author(s):  
Daniel Erskine ◽  
David Koss ◽  
Viktor I. Korolchuk ◽  
Tiago F. Outeiro ◽  
Johannes Attems ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Bodies ◽  
Mitochondrial Diseases ◽  
Model Systems ◽  
Lipid Homeostasis ◽  
Lysosomal Storage ◽  
Iron Storage ◽  
Monogenic Disorders ◽  
Storage Disorders

AbstractAccumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

scholarly journals Dermal fibroblasts from patients with Parkinson’s disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1751 ◽  
Author(s):  
Lucy M Collins ◽  
Janelle Drouin-Ouellet ◽  
Wei-Li Kuan ◽  
Timothy Cox ◽  
Roger A Barker
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Gaucher Disease ◽  
Dermal Fibroblasts ◽  
Skin Fibroblasts ◽  
Autophagic Flux ◽  
Clinical Progression ◽  
Gba Mutations

Background: Recently, the development of Parkinson’s disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.

Sign in / Sign up

Export Citation Format

Share Document