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GBA synuclein

Vassilis E Papadopoulos, Georgia Nikolopoulou, Ivi Antoniadou, Antonia Karachaliou, Giovanna Arianoglou, Evangelia Emmanouilidou, S Pablo Sardi, Leonidas Stefanis, Kostas Vekrellis
Glucocerebrosidase gene (GBA) mutations are the most common genetic contributor to Parkinson's Disease (PD) and are associated with decreased Glucocerebrosidase (GCase) enzymatic activity in PD. PD patients without GBA mutations also exhibit lower levels of GCase activity in the central nervous system (CNS) suggesting a potential contribution of the enzyme activity in disease pathogenesis, possibly by alteration of lysosomal function. α-synuclein, a protein with a central role in PD pathogenesis, has been shown to be secreted partly in association with exosomes...
March 14, 2018: Human Molecular Genetics
Salema B Abul Khair, Nisha R Dhanushkodi, Mustafa T Ardah, Wenfeng Chen, Yufeng Yang, M Emdadul Haque
Background: Mutations in glucocerebrosidase (GBA), a lysosomal enzyme are the most common genetic risk factor for developing Parkinson's disease (PD). We studied how reduced GCase activity affects α-synuclein (α-syn) and its mutants (A30P and A53T) aggregation, neurodegeneration, sleep and locomotor behavior in a fly model of PD. Methods: We developed drosophila with GBA gene knockdown (RNAi) (with reduced GCase activity) that simultaneously expresses either wildtype (WT) or mutants such as A30P or A53T α-syn...
2018: Frontiers in Neuroscience
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
February 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
Matthew E Gegg, Anthony H V Schapira
GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of α-synuclein. A hallmark of PD is the presence intraneuronal protein inclusions called Lewy bodies, which are composed mainly of α-synuclein...
January 31, 2018: FEBS Journal
Michalina Malec-Litwinowicz, Andrzej Plewka, Danuta Plewka, Edyta Bogunia, Michał Morek, Andrzej Szczudlik, Michał Szubiga, Monika Rudzińska-Bar
INTRODUCTION: Parkinson disease (PD) is the common neurodegenerative disease. α-Synuclein (ASN), main aggregating protein in neural cells of CNS in PD, was found in peripheral fluids. Testing ASN in plasma is potential test for diagnose PD, but previous studies are controversial. The aim of this study was to investigate if plasma ASN level may be a valuable biomarker, is the level of plasma ASN concentration different in various motor subtypes of diseases, is there a relation between the level of plasma ASN and the severity of motor symptoms...
November 21, 2017: Neurologia i Neurochirurgia Polska
Aloysius Domingo, Christine Klein
An understanding of the genetic etiology of Parkinson disease (PD) has become imperative for the modern-day neurologist. Although genetic forms cause only a minority of PD, the disease mechanisms they elucidate advance the understanding of idiopathic cases. Moreover, recently identified susceptibility variants contribute to complex-etiology PD and broaden the contribution of genetics beyond familial and early-onset cases. Dominantly inherited monogenic forms mimic idiopathic PD and are caused by mutations or copy number variations of SNCA, LRRK2, and VPS35...
2018: Handbook of Clinical Neurology
Seung Pil Yun, Donghoon Kim, Sangjune Kim, SangMin Kim, Senthilkumar S Karuppagounder, Seung-Hwan Kwon, Saebom Lee, Tae-In Kam, Suhyun Lee, Sangwoo Ham, Jae Hong Park, Valina L Dawson, Ted M Dawson, Yunjong Lee, Han Seok Ko
BACKGROUND: Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA +/L444P ) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin...
January 8, 2018: Molecular Neurodegeneration
Nahid Tayebi, Loukia Parisiadou, Bahafta Berhe, Ashley N Gonzalez, Jenny Serra-Vinardell, Raphael J Tamargo, Emerson Maniwang, Zachary Sorrentino, Hideji Fujiwara, Richard J Grey, Shahzeb Hassan, Yotam N Blech-Hermoni, Chuyu Chen, Ryan McGlinchey, Chrissy Makariou-Pikis, Mieu Brooks, Edward I Ginns, Daniel S Ory, Benoit I Giasson, Ellen Sidransky
Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T ) transgene were crossed with heterozygous null gba mice (gba+/- ). Survival analysis of 84 mice showed that in gba+/- //SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+ //SNCAA53T mice (p-values 0...
December 2017: Molecular Genetics and Metabolism
Nikolaos Papagiannakis, Christos Koros, Maria Stamelou, Athina-Maria Simitsi, Matina Maniati, Roubina Antonelou, Dimitra Papadimitriou, Georgia Dermentzaki, Marina Moraitou, Helen Michelakakis, Leonidas Stefanis
BACKGROUND: Variations of α-synuclein levels or species have been reported in Parkinson's Disease (PD). There has been little systematic examination of erythrocytes, a rich source of α-synuclein. METHODS: Erythrocyte membranes were obtained from PD patients (mutation carriers in the α-synuclein gene (A53T-PD) and glucocerebrosidase gene (GBA-PD) (n=18 each), and patients without known mutations (GU-PD, n=56)), and age-/sex-matched controls (n=56). Levels of monomeric and dimeric α-synuclein were assessed using Western immunoblotting...
November 9, 2017: Neuroscience Letters
Susanne A Schneider, Roy N Alcalay
Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. We review the literature of genetic PD autopsies from cases with molecularly confirmed PD or parkinsonism and summarize main findings on SNCA (n = 25), Parkin (n = 20, 17 bi-allelic and 3 heterozygotes), PINK1 (n = 5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n = 1), LRRK2 (n = 55), GBA (n = 10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n = 8 patients, 2 with PD), MPAN (n = 2), FBXO7, RAB39B, and ATXN2 (SCA2), as well as on 22q deletion syndrome (n = 3)...
November 2017: Movement Disorders: Official Journal of the Movement Disorder Society
Stefanie Lerche, Claudia Schulte, Karin Srulijes, Andrea Pilotto, Tim W Rattay, Ann-Kathrin Hauser, Elke Stransky, Christian Deuschle, Ilona Csoti, Ingolf Lachmann, Henrik Zetterberg, Inga Liepelt-Scarfone, Thomas Gasser, Walter Maetzler, Daniela Berg, Kathrin Brockmann
BACKGROUND: A proportion of idiopathic Parkinson's disease patients (PDidiopathic ) with dementia show altered CSF profiles of amyloid β (Aβ) and Tau. PD patients with Glucocerebrosidase (GBA) mutations (PDGBA ) present with even more cognitive decline than seen in PDidiopathic . OBJECTIVE: The objective of this study was to evaluate whether CSF profiles of Aβ and tau are associated with the prominent cognitive impairment in PDGBA . METHODS: CSF levels of Aβ1-42 , t-Tau, p-Tau, and total alpha-synuclein were assessed in 479 participants (50 PDGBA , 308 PDidiopathic , 121 healthy controls)...
November 2, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
Miriam Sklerov, Un Jung Kang, Christopher Liong, Lorraine Clark, Karen Marder, Michael Pauciulo, William C Nichols, Wendy K Chung, Lawrence S Honig, Etty Cortes, Jean Paul Vonsattel, Roy N Alcalay
BACKGROUND: Multiple system atrophy (MSA) is marked by abnormal inclusions of alpha-synuclein in oligodendrogliocytes. Etiology remains unknown. Variants in the glucocerebrosidase gene have been associated with other synucleinopathies, dementia with Lewy bodies and Parkinson disease. It is unclear whether glucocerebrosidase variants are associated with MSA. OBJECTIVES: To analyze the frequency of glucocerebrosidase gene variants among autopsy-proven cases of MSA at a brain bank in New York City...
July 2017: Movement Disorders Clinical Practice
Grace O'Regan, Ruth-Mary deSouza, Roberta Balestrino, Anthony H Schapira
Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice...
2017: Journal of Parkinson's Disease
S Pablo Sardi, Catherine Viel, Jennifer Clarke, Christopher M Treleaven, Amy M Richards, Hyejung Park, Maureen A Olszewski, James C Dodge, John Marshall, Elina Makino, Bing Wang, Richard L Sidman, Seng H Cheng, Lamya S Shihabuddin
Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, GbaD409V/D409V and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
A Emelyanov, P Andoskin, S Pchelina
This data article presents a dataset of total, oligomeric alpha-synuclein and hemoglobin levels in plasma of drug-naïve PD patients and controls. This is the first attempt to assess the effect of hemolysis rate on oligomeric alpha-synuclein levels in peripheral plasma. The data are associated with the research article "Oligomeric alpha-synuclein and glucocerebrosidase activity levels in GBA-associated Parkinson׳s disease" (Pchelina et al., 2016) [1].
February 2017: Data in Brief
S Pchelina, A Emelyanov, G Baydakova, P Andoskin, K Senkevich, M Nikolaev, I Miliukhina, A Yakimovskii, A Timofeeva, E Fedotova, N Abramycheva, T Usenko, D Kulabukhova, A Lavrinova, A Kopytova, L Garaeva, E Nuzhnyi, S Illarioshkin, E Zakharova
Alpha-synuclein oligomerization plays a key role in the development of Parkinson's disease (PD). Being the most common genetic contributor to PD, glucocerebrosidase 1 (GBA) mutations have been associated with decreased GBA enzymatic activity in PD patients with mutations in the GBA gene (GBA-PD). However, it is unknown whether the activities of other lysosomal hydrolases are being altered in GBA-PD patients and are accompanied by an increase in alpha-synuclein oligomerization. The aim of our study was to estimate GBA enzymatic activity as well as the activities of five other lysosomal hydrolases (galactocerebrosidase, alpha-glucosidase, alpha-galactosidase, sphingomyelinase, alpha-iduronidase) in dried blood spots with assessing plasma oligomeric alpha-synuclein levels in sporadic PD (sPD) patients, in GBA-PD patients and in controls...
January 1, 2017: Neuroscience Letters
Bruno A Benitez, Albert A Davis, Sheng Chih Jin, Laura Ibanez, Sara Ortega-Cubero, Pau Pastor, Jiyoon Choi, Breanna Cooper, Joel S Perlmutter, Carlos Cruchaga
BACKGROUND: Most sequencing studies in Parkinson's disease (PD) have focused on either a particular gene, primarily in familial and early onset PD samples, or on screening single variants in sporadic PD cases. To date, there is no systematic study that sequences the most common PD causing genes with Mendelian inheritance [α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), PARKIN, PTEN-induced putative kinase 1 (PINK1) and DJ-1 (Daisuke-Junko-1)] and susceptibility genes [glucocerebrosidase beta acid (GBA) and microtubule-associated protein tau (MAPT)] identified through genome-wide association studies (GWAS) in a European-American case-control sample (n=815)...
April 19, 2016: Molecular Neurodegeneration
Cynthia A Kelm-Nelson, Sharon A Stevenson, Michelle R Ciucci
Vocal communication deficits are common in Parkinson disease (PD). Widespread alpha-synuclein pathology is a common link between familial and sporadic PD, and recent genetic rat models based on familial genetic links increase the opportunity to explore vocalization deficits and their associated neuropathologies. Specifically, the Pink1 knockout (-/-) rat presents with early, progressive motor deficits, including significant vocal deficits, at 8 months of age. Moreover, this rat model exhibits alpha-synuclein pathology compared to age-matched non-affected wildtype (WT) controls...
May 16, 2016: Neuroscience Letters
Ivanka Marković, Nikola Kresojević, Vladimir S Kostić
Both homo- (causing autosomal-recessive Gaucher's disease; GD) and heterozygous mutations in the glucocerebrosidase gene (GBA) are associated with Parkinson's disease (PD), and represent the most robust known genetic susceptibility factors identified in PD. Since the accumulation of α-synuclein has been considered critical to the pathogenesis of PD among several possible pathways through which glucocerebrosidase (GCase) deficiency may promote the pathogenesis of PD, particular attention was given to the reciprocity with α-synuclein levels, lysosomal dysfunction, endoplasmatic reticulum-Golgi trafficking of GCase, dysregulation of calcium homeostasis and mitochondrial abnormalities...
May 2016: Journal of Neurology
Lluisa Vilageliu, Daniel Grinberg
Gaucher disease is an autosomal recessive lysosomal storage disorder, caused by mutations in the GBA gene. The frequency of Gaucher disease patients and heterozygote carriers that developed Parkinson disease has been found to be above that of the control population. This fact suggests that mutations in the GBA gene can be involved in Parkison's etiology. Analysis of large cohorts of patients with Parkinson disease has shown that there are significantly more cases bearing GBA mutations than those found among healthy individuals...
2017: Current Protein & Peptide Science
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