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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
Hong Jin, Jing Chen, Kai Li, Jin-Ru Zhang, Chen-Chen Gu, Cheng-Jie Mao, Ya-Ping Yang, Feng Wang, Chun-Feng Liu
OBJECTIVES: Pathogenic mutations in the glucocerebrosidase (GBA) gene are associated with Parkinson's disease (PD), of which L444P and N370S are the most frequently observed in patients with PD. The aim of this study was to systematically explore variations in the coding regions of GBA in Han Chinese patients with PD, as well as to expand the GBA mutation spectrum. MATERIAL AND METHODS: A total of 213 Han Chinese patients with PD and 348 controls were enrolled in the study...
March 9, 2018: Neuroscience Letters
Anna Tylki-Szymańska, Paulina Szymańska-Rożek, Piotr Hasiński, Agnieszka Ługowska
Deficiency of beta-glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Macrophages activated by accumulated GlcCer secrete chitotriosidase. Plasma chitotriosidase activity is significantly elevated in patients with active GD and has been suggested to indicate total body Gaucher cell load. There are two biomarkers used to assess the severity of GD - chitotriosidase has been measured for over 20 years, and deacylated GlcCer, known as glucosylsphingosine (GlcSph) is thought to be even more adequate, as it is almost a direct storage substrate...
February 27, 2018: Molecular Genetics and Metabolism
Yuan Zhang, Li Shu, Qiying Sun, Xun Zhou, Hongxu Pan, Jifeng Guo, Beisha Tang
Background: Numerous studies have indicated that there is a possible relationship between GBA variants and Parkinson's disease (PD), however, most of them focused on a few variants such as L444P, N370S. We performed a comprehensive pooled analysis to clarify the relationship between variations of GBA and the risk of PD in different racial groups. Methods : Standard meta-analysis was conducted, including generating inclusion and exclusion criteria, searching literature, extracting and analyzing data. Results : Fifty studies containing 20,267 PD patients and 24,807 controls were included...
2018: Frontiers in Molecular Neuroscience
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
Ana Gámez-Valero, Alex Iranzo, Monica Serradell, Dolores Vilas, Joan Santamaria, Carles Gaig, Ramiro Álvarez, Aurelio Ariza, Eduardo Tolosa, Katrin Beyer
INTRODUCTION: Glucocerebrosidase (GBA) gene variants are associated with the development of the Lewy body disorders (LBD) Parkinson disease (PD) and dementia with Lewy bodies (DLB). Idiopathic REM sleep behavior disorder (IRBD) represents prodromal LBD in most instances. We investigated whether GBA variants are overrepresented in IRBD and if their presence shortens the time to conversion to clinically-defined LBD. METHODS: All GBA coding exons from 69 polysomnography-confirmed IRBD patients and 84 matched controls were sequenced by the Sanger method...
February 21, 2018: Parkinsonism & related Disorders
Athina Simitsi, Christos Koros, Marina Moraitou, Nikos Papagiannakis, Roubina Antonellou, Maria Bozi, Efthalia Angelopoulou, Maria Stamelou, Helen Michelakakis, Leonidas Stefanis
We compared phenotypic characteristics in 35 Greek patients with Parkinson's disease (PD), carriers of GBA1 mutations (GBA-PD), with 35 Genetically Unidentified PD patients (GU-PD). We found a previously reported higher prevalence of cognitive impairment and a little appreciated more frequent bilateral onset of the disease in GBA-PD vs GU-PD. As far as the exposure to environmental factors, linked to PD, is concerned, our study hints to the possibility that pesticide exposure may be more common in GBA-PD patients, and possibly act synergistically with the mutation carrier status to trigger the disease...
2018: Journal of Parkinson's Disease
Anwesha Mandal, Kedar S Prabhavalkar, Lokesh K Bhatt
The connection between the gastrointestinal hormones and the brain has been established many years ago. This relation is termed the gut-brain axis (GBA). The GBA is a bidirectional communication which not only regulates gastrointestinal homeostasis but is also linked with higher emotional and cognitive functions. Hypothalamus plays a critical role in the regulation of energy metabolism, nutrient partitioning and control of feeding behaviors. Various gut hormones are released inside the gastrointestinal tract on food intake...
February 18, 2018: Peptides
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
Naveed Malek, Rimona S Weil, Catherine Bresner, Michael A Lawton, Katherine A Grosset, Manuela Tan, Nin Bajaj, Roger A Barker, David J Burn, Thomas Foltynie, John Hardy, Nicholas W Wood, Yoav Ben-Shlomo, Nigel W Williams, Donald G Grosset, Huw R Morris
OBJECTIVES: To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function. METHODS: We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3...
January 29, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
K Sato, M Sakai, S Hayakawa, Y Sakamoto, Y Kagawa, K Kutara, K Teshima, K Asano, T Watari
BACKGROUND: Gallbladder agenesis (GBA) is extremely rare in dogs. HYPOTHESIS/OBJECTIVES: To describe the history, clinical signs, diagnosis, treatment, and outcomes of dogs with GBA. ANIMALS: Seventeen client-owned dogs with GBA. METHODS: Medical records from 2006 through 2016 were retrospectively reviewed. Dogs were included when GBA was suspected on abdominal ultrasonography and confirmed by gross evaluation. Signalment, clinical signs, clinicopathological data, diagnostic imaging, histopathology, treatment, and outcome were recorded...
January 2018: Journal of Veterinary Internal Medicine
S B Larsen, Z Hanss, R Krüger
Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson's disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular...
January 25, 2018: Cell and Tissue Research
R N Alcalay, P Wolf, O A Levy, U J Kang, C Waters, S Fahn, B Ford, S H Kuo, N Vanegas, H Shah, C Liong, S Narayan, M W Pauciulo, W C Nichols, Z Gan-Or, G A Rouleau, W K Chung, P Oliva, J Keutzer, K Marder, X K Zhang
Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University...
January 21, 2018: Neurobiology of Disease
Patricia García-Sanz, Lorena Orgaz, José M Fuentes, Carlos Vicario, Rosario Moratalla
Lipid and cholesterol metabolism might play a role in the pathogenesis of Parkinson disease (PD). However, the association between cholesterol and PD is not clearly established. Cholesterol accumulation is closely related to the expression of multilamellar bodies (MLBs). Also, cholesterol controls autophagosome transport. Thus, impaired cholesterol and autophagosome trafficking might lead to robust autophagic vacuole accumulation. Our recent work provides the first evidence that the presence of the N370S GBA/GBA1 mutation produces an accumulation of cholesterol, which alters autophagy-lysosome function with the appearance of MLBs, rendering the cell more vulnerable and sensitive to apoptosis...
January 25, 2018: Autophagy
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
Bridget Martinez, Philip V Peplow
Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder, with the clinical main symptoms caused by a loss of dopaminergic neurons in the substantia nigra, corpus striatum and brain cortex. Over 90% of patients with PD have sporadic PD and occur in people with no known family history of the disorder. Currently there is no cure for PD. Treatment with medications to increase dopamine relieves the symptoms but does not slow down or reverse the damage to neurons in the brain. Increasing evidence points to inflammation as a chief mediator of PD with inflammatory response mechanisms, involving microglia and leukocytes, activated following loss of dopaminergic neurons...
December 2017: Neural Regeneration Research
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
Chi-Lin Kuo, Eline van Meel, Kassiani Kytidou, Wouter Willem Kallemeijn, Martin Witte, Herman Stephen Overkleeft, Marta Elena Artola, Johannes Maria Aerts
Glycosidases mediate the fragmentation of glycoconjugates in the body, including the vital recycling of endogenous molecules. Several inherited diseases in man concern deficiencies in lysosomal glycosidases degrading glycosphingolipids. Prominent is Gaucher disease caused by an impaired lysosomal β-glucosidase (glucocerebrosidase, GBA) and resulting in pathological lysosomal storage of glucosylceramide (glucocerebroside) in tissue macrophages. GBA is a retaining glucosidase with a characteristic glycosyl-enzyme intermediate formed during catalysis...
2018: Methods in Enzymology
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