Phenotypic Characteristics in GBA-Associated Parkinson’s Disease: A Study in a Greek Population

Simitsi, Athina Maria; Koros, Christos; Μωραιτου, Μαρινα; Papagiannakis, Nikolaos; Antonellou, Roubina; Bozi, Maria; Angelopoulou, Efthalia; Stamelou, María; Michelakakis, Helen; Stefanis, Leonidas

doi:10.3233/jpd-171221

Cited by 17 publications

(15 citation statements)

References 11 publications

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“…Following the discovery of a higher than expected incidence of PD in Gaucher disease, mutations in the glucocerebrosidase ( GBA ) gene, which encodes for a lysosomal enzyme involved in sphingolipid degradation, are the single largest risk factor for PD; clinically, GBA PD is similar to iPD, albeit with a generally worse cognitive profile, and GBA mutations are found in about 10% of familial or sporadic PD cases in Greece . The study of SNCA A53T and GBA patients represent a unique opportunity to understand PD driven primarily by a single parameter.…”

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confidence: 99%

“…10 Among the different SNCA gene mutations, the highly penetrant SNCA A53T mutation drives clinical features consistent with idiopathic PD (iPD) and represents the 5% of PD patients in Greece who have a high likelihood of a genetic underpinning. 11 Following the discovery of a higher than expected incidence of PD in Gaucher disease, mutations in the glucocerebrosidase (GBA) gene, which encodes for a lysosomal enzyme involved in sphingolipid degradation, are the single largest risk factor for PD; clinically, GBA PD is similar to iPD, albeit with a generally worse cognitive profile, 1,[12][13][14] and GBA mutations are found in about 10% of familial or sporadic PD cases in Greece. 11,15 The study of SNCA A53T and GBA patients represent a unique opportunity to understand PD driven primarily by a single parameter.…”

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confidence: 99%

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Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

et al. 2019

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Background A minimally invasive test for early detection and monitoring of Parkinson's disease (PD) is a highly unmet need for drug development and planning of patient care. Blood plasma represents an attractive source of biomarkers. MicroRNAs (miRNAs) are conserved noncoding RNA molecules that serve as posttranscriptional regulators of gene expression. As opposed to ubiquitously expressed miRNAs that control house‐keeping processes, brain‐enriched miRNAs regulate diverse aspects of neuron development and function. These include neuron‐subtype specification, axonal growth, dendritic morphogenesis, and spine density. Backed by a large number of studies, we now know that the differential expression of neuron‐enriched miRNAs leads to brain dysfunction. Objectives The aim was to identify subsets of brain‐enriched miRNAs with diagnostic potential for familial and idiopathic PD as well as specify the molecular pathways deregulated in PD. Methods Initially, brain‐enriched miRNAs were selected based on literature review and validation studies in human tissues. Subsequently, real‐time reverse transcription polymerase chain reaction was performed in the plasma of 100 healthy controls and 99 idiopathic and 53 genetic (26 alpha‐synucleinA53T and 27 glucocerebrosidase) patients. Statistical and bioinformatics analyses were carried out to pinpoint the diagnostic biomarkers and deregulated pathways, respectively. Results An explicit molecular fingerprint for each of the 3 PD cohorts was generated. Although the idiopathic PD fingerprint was different from that of genetic PD, the molecular pathways deregulated converged between all PD subtypes. Conclusions The study provides a group of brain‐enriched miRNAs that may be used for the detection and differentiation of PD subtypes. It has also identified the molecular pathways deregulated in PD. © 2019 International Parkinson and Movement Disorder Society

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Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

et al. 2019

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“…Furthermore, in red blood cells of GD patients, a positive correlation between the α-syn dimer/monomer ratio and the levels of GC and the GC/Cer ratio was found [29]. There are evidences that GC and glucosylsphyngosine stabilize the toxic α-syn oligomeric intermediates, which in turn, promote the formation of α-syn aggregates [27,29,30]. Accumulated α-syn was also found in the brain of GD mouse models [31,32] and in GBA mutant derived dopaminergic neurons [33].…”

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confidence: 98%

“…Of interest, the T369M and E326K variants, which are not associated to GD even in homozygous state, are associated to PD with an OR of 1.78 and 1.99, respectively [23][24][25]. Furthermore, mutations associated to the neuropathic form of GD are related to more severe motor phenotypes and increased risk of non motor manifestations, including hyposmia, cognitive impairment, and dementia [24,26,27].…”

Section: Gbamentioning

confidence: 99%

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

Paciotti

Albi

Parnetti

et al. 2020

JCM

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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.

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“…GWAS have revealed at least 24 genetic loci that may alter PD risk, and many of them, such as SLC17A5 , ASAH1 and CTSD have been implicated in the autophagy-lysosomal pathways [ 20 , 21 , 22 ]. Notably, heterozygous mutations in the GBA1 gene encoding glucocerebrosidase, whose homozygous mutations cause Gaucher’s disease, constitute the most common genetic risk factor for idiopathic PD [ 23 , 24 ]. The presence of GBA1 mutations has been also shown to affect the clinical phenotype of PD with a more rapid disease progression and cognitive impairment [ 25 ].…”

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confidence: 99%

Arylsulfatase A (ASA) in Parkinson’s Disease: From Pathogenesis to Biomarker Potential

et al. 2020

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Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is a clinically heterogeneous disorder, with obscure etiology and no disease-modifying therapy to date. Currently, there is no available biomarker for PD endophenotypes or disease progression. Accumulating evidence suggests that mutations in genes related to lysosomal function or lysosomal storage disorders may affect the risk of PD development, such as GBA1 gene mutations. In this context, recent studies have revealed the emerging role of arylsulfatase A (ASA), a lysosomal hydrolase encoded by the ARSA gene causing metachromatic leukodystrophy (MLD) in PD pathogenesis. In particular, altered ASA levels have been detected during disease progression, and reduced enzymatic activity of ASA has been associated with an atypical PD clinical phenotype, including early cognitive impairment and essential-like tremor. Clinical evidence further reveals that specific ARSA gene variants may act as genetic modifiers in PD. Recent in vitro and in vivo studies indicate that ASA may function as a molecular chaperone interacting with α-synuclein (SNCA) in the cytoplasm, preventing its aggregation, secretion and cell-to-cell propagation. In this review, we summarize the results of recent preclinical and clinical studies on the role of ASA in PD, aiming to shed more light on the potential implication of ASA in PD pathogenesis and highlight its biomarker potential.

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Phenotypic Characteristics in GBA-Associated Parkinson’s Disease: A Study in a Greek Population

Cited by 17 publications

References 11 publications

Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

Arylsulfatase A (ASA) in Parkinson’s Disease: From Pathogenesis to Biomarker Potential

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