Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

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Abstract

Objectives

To compare the dopaminergic neuronal imaging features of different subtypes of genetic Parkinson's Disease.

Methods

A retrospective study of genetic Parkinson's diseases cases in which DaTSCAN (123I-FP-CIT) had been performed. Specific non-displaceable binding was calculated for bilateral caudate and putamen for each case. The right:left asymmetry index and striatal asymmetry index was calculated.

Results

Scans were available from 37 cases of monogenetic Parkinson's disease (7 glucocerebrosidase (GBA) mutations, 8 alpha-synuclein, 3 LRRK2, 7 PINK1, 12 Parkin). The asymmetry of radioligand uptake for Parkinson's disease with GBA or LRRK2 mutations was greater than that for Parkinson's disease with alpha synuclein, PINK1 or Parkin mutations.

Conclusions

The asymmetry of radioligand uptake in Parkinsons disease associated with GBA or LRRK2 mutations suggests that interactions with additional genetic or environmental factors may be associated with dopaminergic neuronal loss.

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Most cited references 33

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Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

Daniel G Healy, Mario Falchi, Sean S. O’Sullivan … (2008)

Summary Background Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2? Methods Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Findings Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD. Interpretation Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. Funding UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

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Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.

Joseph Mazzulli, You-Hai Xu, Ying Sun … (2011)

Parkinson's disease (PD), an adult neurodegenerative disorder, has been clinically linked to the lysosomal storage disorder Gaucher disease (GD), but the mechanistic connection is not known. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of α-synuclein (α-syn), and results in neurotoxicity through aggregation-dependent mechanisms. Glucosylceramide (GlcCer), the GCase substrate, directly influenced amyloid formation of purified α-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that α-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of α-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies. Copyright © 2011 Elsevier Inc. All rights reserved.

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Parkinson's disease.

Andrew Lees, John Hardy, Tamas Revesz (2009)

Parkinson's disease is a common progressive bradykinetic disorder that can be accurately diagnosed. It is characterised by the presence of severe pars-compacta nigral-cell loss, and accumulation of aggregated alpha-synuclein in specific brain stem, spinal cord, and cortical regions. The main known risk factor is age. Susceptibility genes including alpha-synuclein, leucine rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another important causal factor. Dopamine replacement therapy considerably reduces motor handicap, and effective treatment of associated depression, pain, constipation, and nocturnal difficulties can improve quality of life. Embryonic stem cells and gene therapy are promising research therapeutic approaches.

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Author and article information

Contributors

Wolfdieter Springer: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 23 July 2013

Volume: 8

Issue: 7

Electronic Location Identifier: e69190

Affiliations

[1 ]Department of Clinical Neurosciences, Institute of Neurology, University College London, London, United Kingdom

[2 ]Regional Genetics Unit, Department of Clinical Genetics, Birmingham Women’s Hospital, Birmingham, United Kingdom

[3 ]Department of Neurology, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan

[4 ]Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, Taipei, Taiwan

[5 ]Instituto Israelita de Ensino e Pesquisa Albert Einstein, Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brasil

[6 ]Parkinson's and Movement Disorders Unit, Department of Neurology, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, Spain

[7 ]Center for Neurodegenerative Diseases, University of Salerno, Fisciano Province of Salerno, Italy

[8 ]Sobell Department of Motor Science, Institute of Neurology, University College London, London, United Kingdom

[9 ]Department of Neurology, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil

[10 ]Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands

[11 ]Third Department of Neurology, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

[12 ]Neurology Service and Stroke Unit, General Hospital S. Michele AOB G. Brotzu, Cagliari, Italy

[13 ]Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

[14 ]Division of Movement Disorders, Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM), São Paulo, São Paulo, Brazil

[15 ]Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom

[16 ]Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra, Pamplona, Spain

[17 ]Institute of Biostructure and Bioimaging, CNR, Naples, Italy

[18 ]Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm, Sweden

Mayo Clinic, United States of America

Author notes

* E-mail: a.schapira@ 123456ucl.ac.uk

Competing Interests: Below are the authors' declarations of funding sources, including commercial funders: Rueey-Mei Wu - Analysis of data, revising manuscript. Government research support National Science Council (96-2628-B-002-102-MY3), academic research support not attributed in manuscript National Science Council (98-2628-B-002-072-MY3) National Taiwan University Hospital (100-S1636), on editorial boards Parkinsonism and related disorders, Journal of Formosan Medical Association, Acta Neurologica Taiwanica and no conflicts of interest. Patricia Aguiar - Analysis and interpretation of data. Funding for travel from Roche, government research support FAPESP (grants 2010/19206-0; 2011/18202-3; 2011/14116-5, research grant from Edmond J Safra foundation and no conflicts of interest. Rodrigo Bressan - Analysis and interpretation of data. Research funding from Janssen, Eli Lily, Lundbeck, Novartis, Roche, FAPESP, CNPq, CAPES, Fundação Safra, Fundação ABADS. Shareholder in Radiopharmacus Ltda, Biomolecular Technology Ltda. Speaking fees from Astra Zeneca, Bristol, Janssen, Lundbeck, Roche. No conflicts of interest. Andre Felicio - Analysis and interpretation of data. funding for travel from Roche, Honoraria from Gerson Lehrman group, research funding from Parkinson's society Canada and no conflicts of interest. Henrique Ferraz - Analysis and interpretation of data. Funding for travel from Roche and Novartis and no conflicts of interest. Andrew Lees -Andrew Lees discloses financial support from the Reta Lila Weston Trust, University College London, Parkinson's UK and PSP Association. He is on the specialist board for Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira, Roche, has received consultancy fees from Genus, and honoraria from Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion, BIAL, Noscira and Roche. Laura Silveria-Moriyama - Analysis and interpretation of data. Laura Silveira-Moriyama discloses financial support from the Reta Lila Weston Trust, University College London, University of Campinas, Parkinson's UK and Virginia Keiley Benefaction, and travels grants from UCB, Teva and Boehringer-Ingelheim. Tom Foltynie - Analysis and interpretation of data. Honoraria for speaking at meetings sponsored by St Jude medical, Abbott, Novartis. Grant support from Parkinson's UK, Cure Parkinson's Trust, the European Union and the Brain Research Trust. Anthony HV Schapira - Study design, analysis and interpretation of data, revising manuscript. Receives funding from the United Kingdom Medical Research Council, Wellcome Trust, Parkinson's UK and Kattan Trust. Specialist boards and educational symposia for Orion-Novartis, Teva-Lundbeck, Merck, BI, UCB. AH Schapira is an NIHR Senior Investigator. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: AM AHVS. Performed the experiments: AM SB. Analyzed the data: AM SB. Contributed reagents/materials/analysis tools: AM RMW KYT PCA JMA PB KB OB VB SB RB GC PC AF HBF JH HH MH CI AL OLB NEM PP SP MTP LSM AV TF AHVS. Wrote the paper: AM AHVS.

Article

Publisher ID: PONE-D-13-14393

DOI: 10.1371/journal.pone.0069190

PMC ID: 3720622

PubMed ID: 23935950

SO-VID: b8dee565-9f7e-4494-af36-89884ec0e687

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 2 April 2013

Date accepted : 5 June 2013

Page count

Pages: 7

Funding

This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. AM was supported by a United Kingdom Medical Research Council Research Training Fellowship and Centenary Award (G1001983). AHVS is supported by the Wellcome Trust, Parkinson’s Disease UK and the Kattan Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

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Abstract

Objectives

Methods

Results

Conclusions

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 33

Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.

Parkinson's disease.

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