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Movement Disorders 04/2013; · 4.51 Impact Factor
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ABSTRACT: To date, a plethora of studies have provided evidence favoring an association between Gaucher disease (GD) and Parkinson's disease (PD). GD, the most common lysosomal storage disorder, results from the diminished activity of the lysosomal enzyme β-glucocerebrosidase (GCase), caused by mutations in the β-glucocerebrosidase gene (GBA). Alpha-synuclein (ASYN), a presynaptic protein, has been strongly implicated in PD pathogenesis. ASYN may in part be degraded by the lysosomes and may itself aberrantly impact lysosomal function. Therefore, a putative link between deficient GCase and ASYN, involving lysosomal dysfunction, has been proposed to be responsible for the risk for PD conferred by GBA mutations. In this current work, we aimed to investigate the effects of pharmacological inhibition of GCase on ASYN accumulation/aggregation, as well as on lysosomal function, in differentiated SH-SY5Y cells and in primary neuronal cultures. Following profound inhibition of the enzyme activity, we did not find significant alterations in ASYN levels, or any changes in the clearance or formation of its oligomeric species. We further observed no significant impairment of the lysosomal degradation machinery. These findings suggest that additional interaction pathways together with aberrant GCase and ASYN must govern this complex relation between GD and PD.
PLoS ONE 01/2013; 8(4):e60674. · 4.09 Impact Factor
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Manu Sharma,
John P A Ioannidis,
Jan O Aasly,
Grazia Annesi,
Alexis Brice,
Lars Bertram,
Maria Bozi,
Maria Barcikowska,
David Crosiers,
Carl E Clarke, [......],
Christine Van Broeckhoven,
Karin Wirdefeldt,
Zbigniew Wszolek,
Georgia Xiromerisiou,
Harumi S Yomono,
Kuo-Chu Yueh,
Yi Zhao,
Thomas Gasser,
Demetrius Maraganore,
Rejko Krüger
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ABSTRACT: BACKGROUND: Two recent studies identified a mutation (p.Asp620Asn) in the vacuolar protein sorting 35 gene as a cause for an autosomal dominant form of Parkinson disease . Although additional missense variants were described, their pathogenic role yet remains inconclusive. METHODS AND RESULTS: We performed the largest multi-center study to ascertain the frequency and pathogenicity of the reported vacuolar protein sorting 35 gene variants in more than 15,000 individuals worldwide. p.Asp620Asn was detected in 5 familial and 2 sporadic PD cases and not in healthy controls, p.Leu774Met in 6 cases and 1 control, p.Gly51Ser in 3 cases and 2 controls. Overall analyses did not reveal any significant increased risk for p.Leu774Met and p.Gly51Ser in our cohort. CONCLUSIONS: Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide.
Journal of Medical Genetics 11/2012; 49(11):721-726. · 6.36 Impact Factor
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ABSTRACT: An increasing wealth of data indicates a close relationship between the presynaptic protein alpha-synuclein and Parkinson's disease (PD) pathogenesis. Alpha-synuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular alpha-synuclein has emerged as an additional important factor in this regard. However, the manner of alpha-synuclein degradation in neurons remains contentious. Both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP)-mainly macroautophagy and chaperone-mediated autophagy-have been suggested to contribute to alpha-synuclein turnover. Additionally, other proteases such as calpains, neurosin, and metalloproteinases have been also proposed to have a role in intracellular and extracellular alpha-synuclein processing. Both UPS and ALP activity decline with aging and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in alpha-synuclein accumulation due to impaired clearance. Conversely, increased alpha-synuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In the current review, we summarize the recent findings related to alpha-synuclein degradation, as well as to alpha-synuclein-mediated aberrant effects on protein degradation systems. Identifying the factors that regulate alpha-synuclein association to cellular proteolytic pathways may represent potential targets for therapeutic interventions in PD and related synucleinopathies.
Molecular Neurobiology 09/2012; · 5.74 Impact Factor
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Manu Sharma,
John P A Ioannidis,
Jan O Aasly,
Grazia Annesi,
Alexis Brice,
Christine Van Broeckhoven,
Lars Bertram,
Maria Bozi,
David Crosiers,
Carl Clarke, [......],
Hiroyuki Tomiyama,
Ryan J Uitti,
Karin Wirdefeldt,
Zbigniew Wszolek,
Georgia Xiromerisiou,
Kuo-Chu Yueh,
Yi Zhao,
Thomas Gasser,
Demetrius Maraganore,
Rejko Krüger
Neurology 08/2012; 79:1-9. · 8.31 Impact Factor
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Manu Sharma,
John P A Ioannidis,
Jan O Aasly,
Grazia Annesi,
Alexis Brice,
Christine Van Broeckhoven,
Lars Bertram,
Maria Bozi,
David Crosiers,
Carl Clarke, [......],
Hiroyuki Tomiyama,
Ryan J Uitti,
Karin Wirdefeldt,
Zbigniew Wszolek,
Georgia Xiromerisiou,
Kuo-Chu Yueh,
Yi Zhao,
Thomas Gasser,
Demetrius Maraganore,
Rejko Krüger
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ABSTRACT: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown.
Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry.
In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD.
Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.
Neurology 07/2012; 79(7):659-67. · 8.31 Impact Factor
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ABSTRACT: INTRODUCTION: α-Synuclein is a neuronal presynaptic protein that regulates neurotransmitter release. Genetic, neuropathological, biochemical and animal model data indicate that it plays a major role in Parkinson's disease and other neurodegenerative disorders, acting through a toxic gain of function. Although the mechanism of the toxic function of α-Synuclein is not yet certain, it may involve multiple intracellular targets of the aberrantly misfolded, aggregated protein. It is generally thought that specific soluble oligomeric α-Synuclein species are the offending toxic agents. The total amount of α-Synuclein is a significant factor that determines its toxicity. α-Synuclein can also be secreted and can thus affect neuronal and glial function. Propagation of α-Synuclein pathology via neuron-to-neuron transmission and seeding may also contribute to Parkinson's disease pathogenesis. AREAS COVERED: Key mechanisms of deregulation of α-Synuclein that could be relevant to neurodegeneration, and could offer opportunities for therapeutic intervention. EXPERT OPINION: Counteracting intracellular and extracellular effects of α-Synuclein represents a valid therapeutic target in neurodegeneration. In particular, strategies that target α-Synuclein through limitation of its burden at the transcriptional and post-transcriptional level, inhibition of its aggregation or of aberrant phosphorylation states, immunization or attenuation of its secretion and propagation may be therapeutic options.
Expert opinion on therapeutic targets 04/2012; 16(4):421-32. · 3.72 Impact Factor
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Helen Michelakakis,
Georgia Xiromerisiou,
Efthimios Dardiotis,
Maria Bozi,
Demetrios Vassilatis,
Persa-Maria Kountra,
Gianna Patramani,
Marina Moraitou,
Dimitra Papadimitriou,
Eleftherios Stamboulis, Leonidas Stefanis,
Elias Zintzaras,
Georgios M Hadjigeorgiou
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ABSTRACT: Lysosomal protein 2 (LIMP2), the product of the scavenger receptor class B member 2 (SCARB2) gene, is a ubiquitously expressed transmembrane protein that is the mannose-6-phosphate-independent receptor for glucocerebrosidase (β-GCase); a deficiency in this protein causes Gaucher disease. Several studies have shown a link between mutations in the β-GCase gene and diseases characterized clinically by Parkinsonism and by the presence of Lewy body-related pathology. We hypothesized that genetic variants in the SCARB2 gene could be risk factors for Parkinson's disease (PD). A candidate-gene study of 347 Greek patients with sporadic PD and 329 healthy controls was conducted to investigate the association between 5 polymorphisms in the SCARB2 gene (rs6824953, rs6825004, rs4241591, rs9991821, and rs17234715) and the development of PD. The single-locus analysis for the 5 polymorphisms revealed an association only for the rs6825004 polymorphism: the generalized odds ratio (OR(G) ) was 0.68 (95% confidence interval [CI], 0.51-0.90), and the OR for the allelic test was OR = 0.71 (95% CI, 0.56-0.90). Haplotype analysis showed an association for the GCGGT haplotype (P < .01). Our study supports a genetic contribution of the SCARB2 locus to PD; future studies in larger cohorts are necessary to verify this finding.
Movement Disorders 01/2012; 27(3):400-5. · 4.51 Impact Factor
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Maria Xilouri,
Elli Kyratzi,
Pothitos M Pitychoutis,
Zoi Papadopoulou-Daifoti,
Celine Perier,
Miquel Vila,
Matina Maniati,
Ayse Ulusoy,
Deniz Kirik,
David S Park,
Keiji Wada, Leonidas Stefanis
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ABSTRACT: Genetic studies have implicated the neuronal ubiquitin C-terminal hydrolase (UCH) protein UCH-L1 in Parkinson's disease (PD) pathogenesis. Moreover, the function of UCH-L1 may be lost in the brains of PD and Alzheimer's disease patients. We have previously reported that the UCH-L1 polymorphic variant S18Y, potentially protective against PD in population studies, demonstrates specific antioxidant functions in cell culture. Albeit genetic, biochemical and neuropathological data support an association between UCH-L1, PD, synaptic degeneration and oxidative stress, the relationship between the dopaminergic system and UCH-L1 status remains obscure. In the current study, we have examined the dopaminergic system of mice lacking endogenous UCH-L1 protein (gracile axonal dystrophy mice). Our findings show that the lack of wild-type (WT) UCH-L1 does not influence to any significant degree the dopaminergic system at baseline or following injections of the neurotoxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, using a novel intrastriatal adenoviral injection protocol, we have found that mouse nigral neurons retrogradely transduced with S18Y UCH-L1, but not the WT protein, are significantly protected against MPTP toxicity. Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role.
Human Molecular Genetics 11/2011; 21(4):874-89. · 7.64 Impact Factor
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ABSTRACT: Substantial genetic, neuropathological, and biochemical evidence implicates the presynaptic neuronal protein α-synuclein in Parkinson's disease and related Lewy body disorders. How dysregulation of α-synuclein leads to neurodegeneration is, however, unclear. Soluble oligomeric, but not fully fibrillar, α-synuclein is thought to be toxic. The major neuronal target of aberrant α-synuclein might be the synapse. The effects of aberrant α-synuclein might include alteration of calcium homoeostasis or mitochondrial fragmentation and, in turn, mitochondrial dysfunction, which could link α-synuclein dysfunction to recessive and toxin-induced parkinsonism. α-Synuclein also seems to be linked to other genetic forms of Parkinson's disease, such as those linked to mutations in GBA or LRRK2, possibly through common effects on autophagy and lysosomal function. Finally, α-synuclein is physiologically secreted, and this extracellular form could lead to the spread of pathological accumulations and disease progression. Consequently, factors that regulate the levels, post-translational modifications, specific aberrant cellular effects, or secretion of α-synuclein might be targets for therapy.
The Lancet Neurology 11/2011; 10(11):1015-25. · 23.46 Impact Factor
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Owen A Ross,
Alexandra I Soto-Ortolaza,
Michael G Heckman,
Jan O Aasly,
Nadine Abahuni,
Grazia Annesi,
Justin A Bacon,
Soraya Bardien,
Maria Bozi,
Alexis Brice, [......],
Ryan J Uitti,
Enza Maria Valente,
Simone van de Loo,
Demetrios K Vassilatis,
Carles Vilariño-Güell,
Linda R White,
Karin Wirdefeldt,
Zbigniew K Wszolek,
Ruey-Meei Wu,
Matthew J Farrer
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ABSTRACT: Background The leucine-rich repeat kinase 2 gene (LRRK2) harbours highly penetrant mutations that are linked to familial parkinsonism. However, the extent of its polymorphic variability in relation to risk of Parkinson's disease (PD) has not been assessed systematically. We therefore assessed the frequency of LRRK2 exonic variants in individuals with and without PD, to investigate the role of the variants in PD susceptibility.
LRRK2 was genotyped in patients with PD and controls from three series (white, Asian, and Arab-Berber) from sites participating in the Genetic Epidemiology of Parkinson's Disease Consortium. Genotyping was done for exonic variants of LRRK2 that were identified through searches of literature and the personal communications of consortium members. Associations with PD were assessed by use of logistic regression models. For variants that had a minor allele frequency of 0·5% or greater, single variant associations were assessed, whereas for rarer variants information was collapsed across variants.
121 exonic LRRK2 variants were assessed in 15 540 individuals: 6995 white patients with PD and 5595 controls, 1376 Asian patients and 962 controls, and 240 Arab-Berber patients and 372 controls. After exclusion of carriers of known pathogenic mutations, new independent risk associations were identified for polymorphic variants in white individuals (M1646T, odds ratio 1·43, 95% CI 1·15-1·78; p=0·0012) and Asian individuals (A419V, 2·27, 1·35-3·83; p=0·0011). A protective haplotype (N551K-R1398H-K1423K) was noted at a frequency greater than 5% in the white and Asian series, with a similar finding in the Arab-Berber series (combined odds ratio 0·82, 0·72-0·94; p=0·0043). Of the two previously reported Asian risk variants, G2385R was associated with disease (1·73, 1·20-2·49; p=0·0026), but no association was noted for R1628P (0·62, 0·36-1·07; p=0·087). In the Arab-Berber series, Y2189C showed potential evidence of risk association with PD (4·48, 1·33-15·09; p=0·012).
The results for LRRK2 show that several rare and common genetic variants in the same gene can have independent effects on disease risk. LRRK2, and the pathway in which it functions, is important in the cause and pathogenesis of PD in a greater proportion of patients with this disease than previously believed. These results will help discriminate those patients who will benefit most from therapies targeted at LRRK2 pathogenic activity.
Michael J Fox Foundation and National Institutes of Health.
The Lancet Neurology 08/2011; 10(10):898-908. · 23.46 Impact Factor
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ABSTRACT: Proteasome-mediated proteolysis is a major protein degradation mechanism in cells and its dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, each with the common features of neuronal death and formation of ubiquitinated inclusions found within neurites, the cell body, or nucleus. Previous models of proteasome dysfunction have employed pharmacological inhibition of the catalytic subunits of the 20S proteasome core, or the genetic manipulation of specific subunits resulting in altered proteasome assembly. In this study, we report the use of dominant negative subunits of the 19S regulatory proteasome complex that mediate the recognition of ubiquitinated substrates as well as the removal of the poly-ubiquitin chain. Interestingly, while each mutant subunit-induced inclusion formation, like that seen with pharmacological inhibition of the 20S proteasome, none was able to induce apoptotic death, or trigger activation of macroautophagy, in either dopaminergic cell lines or primary cortical neurons. This finding highlights the dissociation between the mechanisms of neuronal inclusion formation and the induction of cell death, and represents a novel cellular model for Lewy body-like inclusion formation in neurons.
Journal of Neurochemistry 08/2011; 119(3):630-43. · 4.06 Impact Factor
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ABSTRACT: α-Synuclein causes Parkinson's disease if mutated or aberrantly produced in neurons. α-Synuclein-lipid interactions are important for the normal function of the protein, but can also contribute to pathogenesis. We previously reported that deletion of the first 10 N-terminal amino acids dramatically reduced lipid binding in vitro, as well as membrane binding and toxicity in yeast. Here we extend this study to human neuroblastoma SHSY-5Y cells, and find that in these cells the first 10 N-terminal residues do not affect α-synuclein membrane binding, self-association and cell viability, contrary to yeast. Differences in lipid composition, membrane fluidity and cytosolic factors between yeast and neuronal cells may account for the distinct binding behavior of the truncated variant in these two systems. Retinoic acid promotes differentiation and α-synuclein oligomer formation in neuroblastoma cells, while addition of a proteasomal inhibitor induces neurite outgrowth and toxicity to certain wild-type and truncated α-synuclein clones. Yeast recapitulate several features of α-synuclein (patho)biology, but its simplicity sets limitations; verification of yeast results in more relevant model systems is, therefore, essential.
Journal of Neurochemistry 08/2011; 119(2):389-97. · 4.06 Impact Factor
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Marina Moraitou,
Georgios Hadjigeorgiou,
Ioannis Monopolis,
Efthimios Dardiotis,
Maria Bozi,
Demitris Vassilatis,
Lluisa Vilageliu,
Daniel Grinberg,
Georgia Xiromerisiou, Leonidas Stefanis,
Helen Michelakakis
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ABSTRACT: An increasing number of clinical, neuropathological and experimental evidence linking Gaucher disease and a spectrum of synucleinopathies, including Parkinson's disease (PD) has emerged over the last decade. In particular, several studies, despite individual differences, have shown that mutations in the β-glucocerebrosidase gene (GBA) are a risk factor for PD. Recently a study from Northern Greece has shown a significant overrepresentation of such mutations only in patients with early onset PD. In the present study 8 different GBA mutations covering 87% of the mutations identified in Gaucher disease patients diagnosed in Greece were investigated in two ethnic Greek cohorts of patients with sporadic Parkinson's disease. Cohort A included patients residing and originating from Thessaly, Central Greece (n=100) and cohort B included patients residing and/or originating from the greater area of Athens (n=105). Age-gender-ethnicity matched healthy individuals from the same areas were included as controls (n=206). In patients of cohort A 11 carriers of GBA mutations were identified (5/11:N370S, 2/11:L444P, 2/11: D409H;H255Q, 1/11:H255Q, 1/11D409H) as opposed to 3 in the controls (n=105) (1/3:N370S, 1/3:H255Q, 1/3:Y108C) (p=0.021, OR 4.2, 95% CI=1.14-15.54). In patients of cohort B 10 carriers of GBA mutations were identified (4/10:L444P, 4/10:D409H;H255Q, 1/10:N370S, 1/10:IVS10-1G→A) as opposed to 4 in controls (n=101) (3/4:N370S, 1/4:L444P). However the difference was not statistically significant (p=0.113, OR 2.5, 95% CI=0.77-8.42). In both cohorts, patients with PD harboring a GBA mutation had an earlier onset of symptoms than non-carriers (p=0.034, p=0.004). The overall difference in the number of carriers identified in PD patients and controls was statistically significant (p=0.006; OR 3.24; 95% CI=1.35-7.81). The association was reinforced in the early onset PD patients (EOPD; n=28, p=0.000, OR 11.37; 95% CI=3.73-34.6). In conclusion GBA mutations were identified with increased frequency in both geographical cohorts of patients with sporadic PD studied compared to control individuals, with the difference being statistically significant only in cohort A. An impressive association with EOPD was found and one third of the EOPD patients examined harbored a GBA mutation. Qualitative differences regarding the type of mutations and/or their relative frequencies were observed between cohorts A and B of PD patients. Genetic and/or environmental factors may account for the observed differences.
Molecular Genetics and Metabolism 06/2011; 104(1-2):149-52. · 3.19 Impact Factor
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Georgia Xiromerisiou,
Elli Kyratzi,
Efthimios Dardiotis,
Maria Bozi,
Vana Tsimourtou,
Eleftherios Stamboulis,
Styliani Ralli,
Demetrios Vassilatis,
Vanessa Gourbali,
Persa-Maria Kountra,
Kostas Fountas,
Alexandros Papadimitriou, Leonidas Stefanis,
Georgios M Hadjigeorgiou
Movement Disorders 05/2011; 26(10):1955-7. · 4.51 Impact Factor
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ABSTRACT: Alpha-synuclein (SNCA) is a predominantly neuronal protein involved in the control of neurotransmitter release. The levels of SNCA expression are closely linked to the pathogenesis of Parkinson's disease; however, the biochemical pathways and transcriptional elements that control SNCA expression are not well understood. We previously used the model system of neurotrophin-mediated PC12 cell neuronal differentiation to examine these phenomena. Although these studies were informative, they were limited to the use of a cell line; therefore, in the current work, we have turned our attention to cultured primary rat cortical neurons. In these cultures, SNCA expression increased with time in culture, as the neurons mature. Luciferase assays based on transient transfections of fusion constructs encoding components of the transcriptional control region of SNCA identified various promoter areas that have a positive or negative effect on SNCA transcription. Intron 1, previously identified by us as an important regulatory region in the PC12 cell model, cooperates with regions 5' to exon 1 to mediate gene transcription. Using selective pharmacological tools, we find that tyrosine kinase receptors and the phosphatidyl-inositol 3 kinase signaling pathway are involved in mediating these effects. The exogenous application of the neurotrophin brain-derived neurotrophic factor (BDNF) is sufficient on its own to promote the transcriptional activation of SNCA through this pathway, but a neutralizing antibody against BDNF failed to affect SNCA transcription in maturing cultures, suggesting that BDNF is not the main factor involved in maturation-induced SNCA transcription in this model. Further in vivo studies are needed to establish the role of neurotrophin signaling in the control of SNCA transcription.
Journal of Neurochemistry 01/2011; 117(2):275-85. · 4.06 Impact Factor
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ABSTRACT: Macroautophagy and chaperone-mediated autophagy (CMA) are the two main mammalian lysosomal proteolytic systems. In macroautophagy, double-membrane structures engulf organelles and other intracellular constituents through a highly regulated process that involves the formation of autophagic vacuoles and their fusion with lysosomes. In CMA, selected proteins are targeted through a nonvesicular pathway to a transport complex at the lysosomal membrane, through which they are threaded into the lysosomes and degraded. Autophagy is important in development, differentiation, cellular remodelling and survival during nutrient starvation. Increasing evidence suggests that autophagic dysregulation causes accumulation of abnormal proteins or damaged organelles, which is a characteristic of chronic neurodegenerative conditions, such as Parkinson disease (PD). Evidence from post-mortem material, transgenic mice, and animal and cellular models of PD suggests that both major autophagic pathways are malfunctioning. Numerous connections exist between proteins genetically linked to autosomal dominant PD, in particular α-synuclein and LRRK2, and autophagic pathways. However, proteins involved in recessive PD, such as PINK1 and Parkin (PINK2), function in the process of mitophagy, whereby damaged mitochondria are selectively engulfed by macroautophagy. This wealth of new data suggests that both autophagic pathways are potential targets for therapeutic intervention in PD and other related neurodegenerative conditions.
Expert Reviews in Molecular Medicine 01/2011; 13:e8. · 7.14 Impact Factor
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ABSTRACT: The autophagy-lysosomal pathway is a major proteolytic pathway that in mammalian systems mainly comprises of macroautophagy and chaperone-mediated autophagy. The former is relatively non-selective and involves bulk degradation of proteins and organelles, whereas the latter is selective for certain cytosolic proteins. These autophagy pathways are important in development, differentiation, cellular remodeling and survival during nutrient starvation. Autophagy is crucial for neuronal homeostasis and acts as a local housekeeping process, since neurons are post-mitotic cells and require effective protein degradation to prevent accumulation of toxic aggregates. A growing body of evidence now suggests that dysfunction of autophagy causes accumulation of abnormal proteins and/or damaged organelles. Such accumulation has been linked to synaptic dysfunction, cellular stress and neuronal death. Abnormal autophagy may be involved in the pathology of both chronic nervous system disorders, such as proteinopathies (Alzheimer's, Parkinson's, Huntington's disease) and acute brain injuries. Although autophagy is generally beneficial, its aberrant activation may also exert a detrimental role in neurological diseases depending on the environment and the insult, leading to autophagic neuronal death. In this review we summarize the current knowledge regarding the role of autophagy-lysosomal pathway in the central nervous system and discuss the implication of autophagy dysregulation in human neurological diseases and animal models.
CNS & neurological disorders drug targets 11/2010; 9(6):701-19. · 3.57 Impact Factor
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Alexis Elbaz,
Owen A Ross,
John P A Ioannidis,
Alexandra I Soto-Ortolaza,
Frédéric Moisan,
Jan Aasly,
Grazia Annesi,
Maria Bozi,
Laura Brighina,
Marie-Christine Chartier-Harlin, [......],
Peter A Silburn, Leonidas Stefanis,
Ryan J Uitti,
Enza Maria Valente,
Carles Vilariño-Güell,
Karin Wirdefeldt,
Zbigniew K Wszolek,
Georgia Xiromerisiou,
Demetrius M Maraganore,
Matthew J Farrer
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ABSTRACT: We studied the independent and joint effects of the genes encoding alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) in Parkinson disease (PD) as part of a large meta-analysis of individual data from case-control studies participating in the Genetic Epidemiology of Parkinson's Disease (GEO-PD) consortium.
Participants of Caucasian ancestry were genotyped for a total of 4 SNCA (rs2583988, rs181489, rs356219, rs11931074) and 2 MAPT (rs1052553, rs242557) single nucleotide polymorphism (SNPs). Individual and joint effects of SNCA and MAPT SNPs were investigated using fixed- and random-effects logistic regression models. Interactions were studied on both a multiplicative and an additive scale, and using a case-control and case-only approach.
Fifteen GEO-PD sites contributed a total of 5,302 cases and 4,161 controls. All 4 SNCA SNPs and the MAPT H1-haplotype-defining SNP (rs1052553) displayed a highly significant marginal association with PD at the significance level adjusted for multiple comparisons. For SNCA, the strongest associations were observed for SNPs located at the 3' end of the gene. There was no evidence of statistical interaction between any of the 4 SNCA SNPs and rs1052553 or rs242557, neither on the multiplicative nor on the additive scale.
This study confirms the association between PD and both SNCA SNPs and the H1 MAPT haplotype. It shows, based on a variety of approaches, that the joint action of variants in these 2 loci is consistent with independent effects of the genes without additional interacting effects.
Annals of Neurology 10/2010; 69(5):778-92. · 11.09 Impact Factor
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ABSTRACT: Psychotic features in patients with Parkinson's Disease usually present as visual hallucinations against a background of cognitive deterioration and dopaminomimetic therapy. Isolated delusions are rare. We report here 4 patients with Parkinson's Disease who developed a delusional syndrome resembling schizophreniform psychosis in the absence of changes in alertness, visual hallucinations or dementia. We suggest that this syndrome may be more common than previously recognized, and that it may be related to the use of dopaminergic medications and environmental triggers on a background of a susceptible individual. This syndrome suggests interesting parallels with the pathophysiology of amphetamine-induced psychosis and schizophrenia.
Parkinsonism & Related Disorders 09/2010; 16(8):550-2. · 3.80 Impact Factor
