scholarly journals Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease

Brain ◽  
2020 ◽  
Vol 143 (4) ◽  
pp. 1190-1205 ◽  
Author(s):  
Yutaka Oji ◽  
Taku Hatano ◽  
Shin-Ichi Ueno ◽  
Manabu Funayama ◽  
Kei-ichi Ishikawa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mutation Screening ◽  
Intracellular Localization ◽  
Genetic Mutation ◽  
Lysosomal Storage Disorders ◽  
Autophagic Flux ◽  
Lysosomal Storage ◽  
Causative Gene ◽  
Storage Disorders

Abstract Recently, the genetic variability in lysosomal storage disorders has been implicated in the pathogenesis of Parkinson’s disease. Here, we found that variants in prosaposin (PSAP), a rare causative gene of various types of lysosomal storage disorders, are linked to Parkinson’s disease. Genetic mutation screening revealed three pathogenic mutations in the saposin D domain of PSAP from three families with autosomal dominant Parkinson’s disease. Whole-exome sequencing revealed no other variants in previously identified Parkinson’s disease-causing or lysosomal storage disorder-causing genes. A case-control association study found two variants in the intronic regions of the PSAP saposin D domain (rs4747203 and rs885828) in sporadic Parkinson’s disease had significantly higher allele frequencies in a combined cohort of Japan and Taiwan. We found the abnormal accumulation of autophagic vacuoles, impaired autophagic flux, altered intracellular localization of prosaposin, and an aggregation of α-synuclein in patient-derived skin fibroblasts or induced pluripotent stem cell-derived dopaminergic neurons. In mice, a Psap saposin D mutation caused progressive motor decline and dopaminergic neurodegeneration. Our data provide novel genetic evidence for the involvement of the PSAP saposin D domain in Parkinson’s disease.

The Lysosome and Nonmotor Symptoms: Linking Parkinson's Disease and Lysosomal Storage Disorders

2020 ◽  
Vol 35 (12) ◽  
pp. 2150-2155
Author(s):  
Shani Blumenreich ◽  
Bethan J. Jenkins ◽  
Or B. Barav ◽  
Ivan Milenkovic ◽  
Anthony H. Futerman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Nonmotor Symptoms ◽  
Storage Disorders

Possible Involvement of Genes Related to Lysosomal Storage Disorders in the Pathogenesis of Parkinson’s Disease

2019 ◽  
Vol 53 (1) ◽  
pp. 24-31
Author(s):  
M. M. Rudenok ◽  
A. Kh. Alieva ◽  
M. A. Nikolaev ◽  
A. A. Kolacheva ◽  
M. V. Ugryumov ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Storage Disorders

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.

P.101 Involvement of the genes related to lysosomal storage disorders in GBA-associated Parkinson's disease

2021 ◽  
Vol 44 ◽  
pp. S1-S2
Author(s):  
A. Bezrukova ◽  
D. Bogdanova ◽  
K. Basharova ◽  
K. Senkevich ◽  
E. Gracheva ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Storage Disorders

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 Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders

2018 ◽  
Author(s):  
Jarmila Králová ◽  
Michal Jurášek ◽  
Lucie Krčová ◽  
Bohumil Dolenský ◽  
Ivan Novotný ◽  
...  
Keyword(s):  
Genetic Mutation ◽  
Lysosomal Storage Disorders ◽  
Cholesterol Homeostasis ◽  
Fluorescence Labeling ◽  
Lysosomal Storage ◽  
Animal Cells ◽  
Design And Synthesis ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Storage Disorders

AbstractThe monitoring of intracellular cholesterol homeostasis and trafficking is of great importance because their imbalance leads to many pathologies. Reliable tools for cholesterol detection are in demand. This study presents the design and synthesis of fluorescent probes for cholesterol recognition and demonstrates their selectivity by a variety of methods. The construction of dedicated library of 14 probes was based on heterocyclic (pyridine)-sterol derivatives with various attached fluorophores. The most promising probe, a P1-BODIPY conjugate FP-5, was analyzed in detail and showed an intensive labeling of cellular membranes followed by intracellular redistribution into various cholesterol rich organelles and vesicles. FP-5 displayed a stronger signal, with faster kinetics, than the commercial TF-Chol probe. In addition, cells with pharmacologically disrupted cholesterol transport, or with a genetic mutation of cholesterol transporting protein NPC1, exhibited strong and fast FP-5 labeling in the endo/lysosomal compartment, co-localizing with filipin staining of cholesterol. Hence, FP-5 has high potential as a new probe for monitoring cholesterol trafficking and its disorders.Significance statementCholesterol is a vital steroid molecule with many important functions in animal cells. Although its dysregulation is associated with an expanding list of clinically important pathologies, the study of its role is limited by a lack of reliable tools for live intracellular monitoring. This study demonstrates the applicability of a novel class of heterocyclic sterol probes. These probes exhibit fast cellular uptake with effective fluorescence labeling of sterol species in a variety of living cells, without a need for artificial carriers. When applied to Niemann-Pick disease type C1 cells, they identified massive accumulation of cholesterol in the endosome/lysosome compartment. Thus, several probes from the same series can also be used for visualizing lysosomal storage disorders and sterol transporting pathologies.

scholarly journals Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson’s Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12740
Author(s):  
Oluwanifemi Shola-Dare ◽  
Shelby Bailess ◽  
Carlos C. Flores ◽  
William M. Vanderheyden ◽  
Jason R. Gerstner
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Optimal Dose ◽  
Phenotypic Traits ◽  
Autophagic Flux ◽  
Lysosomal Storage ◽  
Therapeutic Approaches ◽  
Protein Levels ◽  
Gba Mutations

Parkinson’s Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD/PD in animal models may provide an opportunity for treating neurological manifestations of GD/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1ΔTT/ΔTT). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 μM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1ΔTT/ΔTT mutant flies, compared to GBA1+/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins.

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