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Parkinson Disease: HELP
Articles by Anthony Henry Vernon Schapira
Based on 90 articles published since 2008
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Between 2008 and 2019, A. H. V. Schapira wrote the following 90 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Editorial Targeting mitochondria for neuroprotection in Parkinson disease. 2014

Schapira, Anthony H V / Patel, Sandip. ·Department of Clinical Neurosciences, Institute of Neurology, University College London, London, England. · Department of Cell and Developmental Biology, University College London, London, England. ·JAMA Neurol · Pubmed #24664140.

ABSTRACT: -- No abstract --

2 Editorial Optimizing treatment for Parkinson's disease. 2012

Schapira, A H V / Tan, E K. · ·Eur J Neurol · Pubmed #23157243.

ABSTRACT: -- No abstract --

3 Editorial The management of Parkinson's disease - what is new? 2011

Schapira, A H V. · ·Eur J Neurol · Pubmed #21255196.

ABSTRACT: -- No abstract --

4 Review Glucocerebrosidase and Parkinson Disease: Molecular, Clinical, and Therapeutic Implications. 2018

Balestrino, Roberta / Schapira, Anthony H V. ·1 Department of Neuroscience, University of Turin, Turin, Italy. · 2 Department of Clinical Neurosciences, UCL Institute of Neurology, Royal Free Campus, London, UK. ·Neuroscientist · Pubmed #29400127.

ABSTRACT: 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. The molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are multiple and not yet fully elucidated, they include alpha-synuclein aggregation, lysosomal-autophagy dysfunction and endoplasmic reticulum stress. Moreover, dysfunction of glucocerebrosidase has also been demonstrated in non-GBA PD, suggesting its interaction with other pathogenic mechanisms. Therefore, GBA enzyme function represents an interesting pharmacological target for PD. Cell and animal models suggest that increasing GBA enzyme activity can reduce alpha-synuclein levels. Clinical trials of ambroxol, a glucocerebrosidase chaperone, are currently ongoing in PD and PD dementia, as is a trial of substrate reduction therapy. The aim of this review is to summarise the main features of GBA-PD and discuss the implications of glucocerebrosidase modulation on PD pathogenesis.

5 Review Insights into the structural biology of Gaucher disease. 2017

Smith, Laura / Mullin, Stephen / Schapira, Anthony H V. ·Department of Clinical Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK. · Department of Clinical Neurosciences, Institute of Neurology, University College London, London, NW3 2PF, UK. Electronic address: a.schapira@ucl.ac.uk. ·Exp Neurol · Pubmed #28923368.

ABSTRACT: Gaucher disease, the most common lysosomal storage disorder, is caused by mutations in the gene encoding the acid-β-glucosidase lysosomal hydrolase enzyme that cleaves glucocerebroside into glucose and ceramide. Reduced enzyme activity and impaired structural stability arise due to >300 known disease-causing mutations. Several of these mutations have also been associated with an increased risk of Parkinson disease (PD). Since the discovery of the acid-β-glucosidase X-ray structure, there have been major advances in our understanding of the structural properties of the protein. Analysis of specific residues has provided insight into their functional and structural importance and provided insight into the pathogenesis of Gaucher disease and the contribution to PD. Disease-causing mutations are positioned throughout the acid-β-glucosidase structure, with many located far from the active site and thus retaining some enzymatic activity however, thus far no clear relationship between mutation location and disease severity has been established. Here, we review the crystal structure of acid-β-glucosidase, while highlighting important structural aspects of the protein in detail. This review discusses the structural stability of acid-β-glucosidase, which can be altered by pH and glycosylation, and explores the relationship between known Gaucher disease and PD mutations, structural stability and disease severity.

6 Review Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy. 2017

Obeso, J A / Stamelou, M / Goetz, C G / Poewe, W / Lang, A E / Weintraub, D / Burn, D / Halliday, G M / Bezard, E / Przedborski, S / Lehericy, S / Brooks, D J / Rothwell, J C / Hallett, M / DeLong, M R / Marras, C / Tanner, C M / Ross, G W / Langston, J W / Klein, C / Bonifati, V / Jankovic, J / Lozano, A M / Deuschl, G / Bergman, H / Tolosa, E / Rodriguez-Violante, M / Fahn, S / Postuma, R B / Berg, D / Marek, K / Standaert, D G / Surmeier, D J / Olanow, C W / Kordower, J H / Calabresi, P / Schapira, A H V / Stoessl, A J. ·HM CINAC, Hospital Universitario HM Puerta del Sur, Mostoles, Madrid, Spain. · Universidad CEU San Pablo, Madrid, Spain. · CIBERNED, Madrid, Spain. · Department of Neurology, Philipps University, Marburg, Germany. · Parkinson's Disease and Movement Disorders Department, HYGEIA Hospital and Attikon Hospital, University of Athens, Athens, Greece. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA. · Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. · Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, Toronto, Canada. · Department of Medicine, University of Toronto, Toronto, Canada. · Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Parkinson's Disease and Mental Illness Research, Education and Clinical Centers (PADRECC and MIRECC), Corporal Michael J. Crescenz Veteran's Affairs Medical Center, Philadelphia, Pennsylvania, USA. · Medical Sciences, Newcastle University, Newcastle, UK. · Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia. · School of Medical Sciences, University of New South Wales and Neuroscience Research Australia, Sydney, Australia. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, Institut des Maladies Neurodégénératives, Bordeaux, France. · China Academy of Medical Sciences, Institute of Lab Animal Sciences, Beijing, China. · Departments of Neurology, Pathology, and Cell Biology, the Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA. · Columbia Translational Neuroscience Initiative, Columbia University, New York, New York, USA. · Institut du Cerveau et de la Moelle épinière - ICM, Centre de NeuroImagerie de Recherche - CENIR, Sorbonne Universités, UPMC Univ Paris 06, Inserm U1127, CNRS UMR 7225, Paris, France. · Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Clinical Sciences Department, Newcastle University, Newcastle, UK. · Department of Nuclear Medicine, Aarhus University, Aarhus, Denmark. · Human Neurophysiology, Sobell Department, UCL Institute of Neurology, London, UK. · Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA. · Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson's disease, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Movement Disorders and Neuromodulation Center, Department of Neurology, University of California-San Francisco, San Francisco, California, USA. · Parkinson's Disease Research, Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA. · Veterans Affairs Pacific Islands Health Care System, Honolulu, Hawaii, USA. · Parkinson's Institute, Sunnyvale, California, USA. · Institute of Neurogenetics, University of Luebeck, Luebeck, Germany. · Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Department of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada. · Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian Albrechts University Kiel, Kiel, Germany. · Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Jerusalem, Israel. · Edmond and Lily Safra Center for Brain Sciences, The Hebrew University, Jerusalem, Israel. · Department of Neurosurgery, Hadassah University Hospital, Jerusalem, Israel. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Barcelona, Spain. · Department of Medicine, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Barcelona, Spain. · Movement Disorders Clinic, Clinical Neurodegenerative Research Unit, Mexico City, Mexico. · Instituto Nacional de Neurología y Neurocirugía, Mexico City, Mexico. · Department of Neurology, Columbia University Medical Center, New York, New York, USA. · Department of Neurology, McGill University, Montreal General Hospital, Montreal, Quebec, Canada. · Klinik für Neurologie, UKSH, Campus Kiel, Christian-Albrechts-Universität, Kiel, Germany. · Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA. · Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, New York, USA. · Research Center for Brain Repair, Rush University Medical Center, Chicago, Illinois, USA. · Neuroscience Graduate Program, Rush University Medical Center, Chicago, Illinois, USA. · Neurological Clinic, Department of Medicine, Hospital Santa Maria della Misericordia, University of Perugia, Perugia, Italy. · Laboratory of Neurophysiology, Santa Lucia Foundation, IRCCS, Rome, Italy. · University Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, UK. · Pacific Parkinson's Research Centre, Division of Neurology & Djavadf Mowafaghian Centre for Brain Health, University of British Columbia, British Columbia, Canada. · Vancouver Coastal Health, Vancouver, British Columbia, Canada. ·Mov Disord · Pubmed #28887905.

ABSTRACT: This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

7 Review Nonmotor Symptoms in Experimental Models of Parkinson's Disease. 2017

Titova, Nataliya / Schapira, Anthony H V / Chaudhuri, K Ray / Qamar, Mubasher A / Katunina, Elena / Jenner, Peter. ·Federal State Budgetary Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University" of the Ministry of Healthcare of the Russian Federation, Moscow, Russia. Electronic address: nattitova@yandex.ru. · UCL Institute of Neurology, London, United Kingdom. · National Parkinson Foundation International Centre of Excellence, King's College London and King's College Hospital, London, United Kingdom; The Maurice Wohl Clinical Neuroscience Institute, King's College London, National Institute for Health Research (NIHR) South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom. · Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Science, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom. ·Int Rev Neurobiol · Pubmed #28802936.

ABSTRACT: Nonmotor symptoms of Parkinson's disease (PD) range from neuropsychiatric, cognitive to sleep and sensory disorders and can arise from the disease process as well as from drug treatment. The clinical heterogeneity of nonmotor symptoms of PD is underpinned by a wide range of neuropathological and molecular pathology, affecting almost the entire range of neurotransmitters present in brain and the periphery. Understanding the neurobiology and pathology of nonmotor symptoms is crucial to the effective treatment of PD and currently a key unmet need. This bench-to-bedside translational concept can only be successful if robust animal models of PD charting the genesis and natural history of nonmotor symptoms can be devised. Toxin-based and transgenic rodent and primate models of PD have given us important clues to the underlying basis of motor symptomatology and in addition, can provide a snapshot of some nonmotor aspects of PD, although the data are far from complete. In this chapter, we discuss some of the nonmotor aspects of the available experimental models of PD and how the development of robust animal models to understand and treat nonmotor symptoms needs to become a research priority.

8 Review Non-motor features of Parkinson disease. 2017

Schapira, Anthony H V / Chaudhuri, K Ray / Jenner, Peter. ·Department of Clinical Neurosciences, University College London (UCL) Institute of Neurology, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. · National Parkinson Foundation International Centre of Excellence, King's College Hospital, King's College London, Camberwell Road, London SE5 9RS, UK. · Neurodegenerative Diseases Research Group, Institute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King's College London, Newcomen Street, London SE1 1UL, UK. ·Nat Rev Neurosci · Pubmed #28592904.

ABSTRACT: Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD.

9 Review Molecular changes in the postmortem parkinsonian brain. 2016

Toulorge, Damien / Schapira, Anthony H V / Hajj, Rodolphe. ·Encefa, Le Kremlin Bicêtre, France. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · Department of Discovery, Pharnext, Issy-Les-Moulineaux, France. rhajj@pharnext.com. ·J Neurochem · Pubmed #27381749.

ABSTRACT: Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by 'reverse biochemistry' i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD. Parkinson's is accompanied by multiple changes in the brain that are responsible for the progression of the disease. We describe here the molecular alterations occurring in postmortem brains and classify them as: Neurotransmitters and neurotrophic factors; Lewy bodies and Parkinson's-linked genes; Transition metals, calcium and calcium-binding proteins; Inflammation; Mitochondrial abnormalities and oxidative stress; Abnormal protein removal and degradation; Apoptosis and transduction pathways. This article is part of a special issue on Parkinson disease.

10 Review Glucocerebrosidase in Parkinson's disease: Insights into pathogenesis and prospects for treatment. 2016

Schapira, Anthony H V / Chiasserini, Davide / Beccari, Tommaso / Parnetti, Lucilla. ·University Department of Clinical Neurosciences, UCL Institute of Neurology, London, United Kingdom. · Department of Medicine, section of Neurology, University of Perugia, Perugia, Italy. · Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy. ·Mov Disord · Pubmed #27091307.

ABSTRACT: PD involves several converging pathogenetic pathways to neurodegeneration; highlighted in specific cases by genetic mutations causing familial PD. Numerically, the most important genetic mutations associated with PD are those of the glucocerebrosidase gene. Approximately 10% of PD patients carry glucocerebrosidase mutations. This observation has enhanced focus on the autophagy-lysosome system as important in pathogenesis. The relationship of the glucocerebrosidase pathway to the cause and progression of PD highlights the potential to use abnormalities identified as biomarkers and modify glucocerebrosidase activity or substrate accumulation as neuroprotection. Biomarkers relevant to the glucocerebrosidase pathway, for example, enzyme activity and substrate levels, may be identified in blood, urine, and CSF. These may be combined with clinical features to help identify mutation carriers that are at increased risk of PD. The molecular mechanisms by which glucocerebrosidase mutations may result in PD are not fully understood. There is evidence accumulating that there is a reciprocal interaction between glucocerebrosidase and alpha-synuclein levels. This interaction may potentially be used to increase glucocerebrosidase enzyme activities and therefore reduce alpha-synuclein levels to modify the course of PD. Substrate reduction therapy may be an alternative strategy, particularly if membrane abnormalities underlie the organellar dysfunction in PD neurodegeneration. © 2016 International Parkinson and Movement Disorder Society.

11 Review The relationship between glucocerebrosidase mutations and Parkinson disease. 2016

Migdalska-Richards, Anna / Schapira, Anthony H V. ·Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. · Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. a.schapira@ucl.ac.uk. ·J Neurochem · Pubmed #26860875.

ABSTRACT: Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease, whereas Gaucher disease (GD) is the most frequent lysosomal storage disorder caused by homozygous mutations in the glucocerebrosidase (GBA1) gene. Increased risk of developing PD has been observed in both GD patients and carriers. It has been estimated that GBA1 mutations confer a 20- to 30-fold increased risk for the development of PD, and that at least 7-10% of PD patients have a GBA1 mutation. To date, mutations in the GBA1 gene constitute numerically the most important risk factor for PD. The type of PD associated with GBA1 mutations (PD-GBA1) is almost identical to idiopathic PD, except for a slightly younger age of onset and a tendency to more cognitive impairment. Importantly, the pathology of PD-GBA1 is identical to idiopathic PD, with nigral dopamine cell loss, Lewy bodies, and neurites containing alpha-synuclein. The mechanism by which GBA1 mutations increase the risk for PD is still unknown. However, given that clinical manifestation and pathological findings in PD-GBA1 patients are almost identical to those in idiopathic PD individuals, it is likely that, as in idiopathic PD, alpha-synuclein accumulation, mitochondrial dysfunction, autophagic impairment, oxidative and endoplasmic reticulum stress may contribute to the development and progression of PD-GBA1. Here, we review the GBA1 gene, its role in GD, and its link with PD. The impact of glucocerebrosidase 1 (GBA1) mutations on functioning of endoplasmic reticulum (ER), lysosomes, and mitochondria. GBA1 mutations resulting in production of misfolded glucocerebrosidase (GCase) significantly affect the ER functioning. Misfolded GCase trapped in the ER leads to both an increase in the ubiquitin-proteasome system (UPS) and the ER stress. The presence of ER stress triggers the unfolded protein response (UPR) and/or endoplasmic reticulum-associated degradation (ERAD). The prolonged activation of UPR and ERAD subsequently leads to increased apoptosis. The presence of misfolded GCase in the lysosomes together with a reduction in wild-type GCase levels lead to a retardation of alpha-synuclein degradation via chaperone-mediated autophagy (CMA), which subsequently results in alpha-synuclein accumulation and aggregation. Impaired lysosomal functioning also causes a decrease in the clearance of autophagosomes, and so their accumulation. GBA1 mutations perturb normal mitochondria functioning by increasing generation of free radical species (ROS) and decreasing adenosine triphosphate (ATP) production, oxygen consumption, and membrane potential. GBA1 mutations also lead to accumulation of dysfunctional and fragmented mitochondria. This article is part of a special issue on Parkinson disease.

12 Review Glucocerebrosidase and Parkinson disease: Recent advances. 2015

Schapira, Anthony H V. ·Department of Clinical Neurosciences, UCL Institute of Neurology, UCL Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom. Electronic address: a.schapira@ucl.ac.uk. ·Mol Cell Neurosci · Pubmed #25802027.

ABSTRACT: Mutations of the glucocerebrosidase (GBA) gene are the most important risk factor yet discovered for Parkinson disease (PD). Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder. Heterozygous mutations have not until recently been thought to be associated with any pathological process. However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose. Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced. GBA-associated PD is clinically indistinguishable from idiopathic PD, except for slightly earlier age of onset and a greater frequency of cognitive impairment. Pathological and imaging features, and response to pharmacotherapy are identical to idiopathic PD. GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress. Both mechanisms may be relevant in GD and PD pathogenesis and lead to impaired lysosomal function. Of particular relevance to PD is the interaction of glucocerebrosidase enzyme (GCase) with alpha-synuclein (SNCA). There appears to be a bi-directional reciprocal relationship between GCase levels and those of SNCA. Thus reduced GCase in GBA mutation PD brain is associated with increased SNCA, and increased SNCA deposition is associated with reduced GCase even in GBA wild-type PD brains. It is noteworthy that GBA mutations are also associated with an increase in risk for dementia with Lewy bodies, another synucleinopathy. It has been suggested that the relationship between GCase and SNCA may be leveraged to reduce SNCA levels in PD by enhancing GCase levels and activity. This hypothesis has been confirmed in GBA mutant mice, PD patient fibroblasts and cells with SNCA overexpression, and offers an important target pathway for future neuroprotection therapy in PD. This article is part of a Special Issue entitled 'Neuronal Protein'.

13 Review Pathogenic mechanisms of neurodegeneration in Parkinson disease. 2015

Mullin, Stephen / Schapira, Anthony H V. ·Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, Hampstead, London NW3 2PF, UK. · Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, Hampstead, London NW3 2PF, UK. Electronic address: a.schapira@ucl.ac.uk. ·Neurol Clin · Pubmed #25432720.

ABSTRACT: The last 2 decades represent a period of unparalleled advancement in the understanding of the pathogenesis of Parkinson disease (PD). The discovery of several forms of familial parkinsonism with mendelian inheritance has elucidated insights into the mechanisms underlying the degeneration of dopaminergic neurons of the substantia nigra that histologically characterize PD. α-Synuclein, the principal component of Lewy bodies, remains the presumed pathogen at the heart of the current model; however, concurrently, a diverse range of other mechanisms have been implicated. The creation of a coherent disease model will be crucial to the development of effective disease modifying therapies for sporadic PD.

14 Review Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives. 2014

Schapira, Anthony H V / Olanow, C Warren / Greenamyre, J Timothy / Bezard, Erwan. ·Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. Electronic address: a.schapira@ucl.ac.uk. · Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY, USA. · Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15260, USA. · Université de Bordeaux, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, 33000 Bordeaux, France. ·Lancet · Pubmed #24954676.

ABSTRACT: Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of α-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels.

15 Review Early versus delayed initiation of pharmacotherapy in Parkinson's disease. 2014

Löhle, Matthias / Ramberg, Carl-Johan / Reichmann, Heinz / Schapira, Anthony H V. ·Department of Neurology, Dresden University of Technology, Dresden, Germany. ·Drugs · Pubmed #24756431.

ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and pathologically is characterised by a progressive loss of dopaminergic cells of the nigrostriatal pathway. Clinically, PD is mainly defined by the presence of the motor symptoms of bradykinesia, rigidity, rest tremor and postural instability, but non-motor symptoms such as depression, dementia and autonomic disturbances are recognised as integral parts of the disease. Although pharmacotherapy for PD was introduced almost 50 years ago, and has improved significantly over the intervening period, the timing of initiation of treatment in newly diagnosed PD remains controversial. While some physicians favour an early start of pharmacotherapy at or soon after diagnosis, others prefer to delay pharmacological treatment until a certain degree of disability has developed. This article aims to discuss the advantages and disadvantages of both strategies by exploring their effects on symptoms, disease progression and quality of life. Although the data on putative disease-modifying effects of early pharmacological intervention in PD are still inconclusive, we believe that the most important indication for an early initiation of anti-parkinsonian treatment should be to maintain the quality of life of PD patients and to secure their socioeconomic status as long as possible.

16 Review Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. 2013

Beavan, Michelle S / Schapira, Anthony H V. ·Department of Clinical Neurosciences, University College London Institute of Neurology , London NW3 2PF , United Kingdom. ·Ann Med · Pubmed #24219755.

ABSTRACT: Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease with a lifetime risk in the UK population of almost 5%. An association between PD and Gaucher disease (GD) derived from the observation that GD patients and their heterozygous carrier relatives were at increased risk of PD. GD is an autosomal recessive lysosomal storage disorder caused by homozygous mutations in the gene encoding glucocerebrosidase (GBA). Approximately 5%-10% of PD patients have GBA mutations, making these mutations numerically the most important genetic predisposing risk factor for the development of PD identified to date. GBA mutations result in a phenotype that is virtually indistinguishable clinically, pharmacologically, and pathologically from sporadic PD, except GBA mutations result in a slightly earlier age of onset and more frequent cognitive impairment among PD patients. The mechanisms by which GBA mutations result in PD are not yet understood. Both reduced glucocerebrosidase enzyme (GCase) activity with lysosomal dysfunction, and unfolded protein response (UPR) with endoplasmic reticulum-associated degradation (ERAD) and stress are considered contributory.

17 Review Therapeutic prospects for Parkinson disease. 2013

Olanow, C Warren / Schapira, Anthony H V. ·Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY. ·Ann Neurol · Pubmed #24038341.

ABSTRACT: Dopaminergic therapies such as levodopa have provided benefit for millions of patients with Parkinson's disease (PD) and revolutionized the treatment of this disorder. However patients continue to experience disability despite the best of modern treatment. Dopaminergic and surgical therapies are associated with potentially serious side effects. Non-motor and non-dopaminergic features such as freezing, falling, and dementia are not adequately controlled with available medications and represent the major source of disability for advanced patients. And, the disease continues to relentlessly progress. Major therapeutic unmet needs include a dopaminergic therapy that is not associated with serious side effects, a therapy that addresses the non-motor and non-dopaminergic features of the disease, and a disease-modifying therapy that slows or stops disease progression. This review will consider current attempts to address these issues and the obstacles that must be overcome in order to develop more effective therapies for PD.

18 Review Recent developments in biomarkers in Parkinson disease. 2013

Schapira, Anthony H V. ·Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. a.schapira@medsch.ucl.ac.uk ·Curr Opin Neurol · Pubmed #23823465.

ABSTRACT: PURPOSE OF REVIEW: Parkinson disease is the second most common neurodegenerative disease after Alzheimer disease, and current demographic trends indicate a life-time risk approaching 4% and predict a doubling of prevalence by 2030. Strategies are being developed to apply recent advances in our understanding of the cause of Parkinson disease to the development of biomarkers that will enable the identification of at-risk individuals, enable early diagnosis and reflect the progression of disease. The latter will be particularly important for the testing of disease-modifying therapies. This review summarizes recent advances in Parkinson disease biomarker development. RECENT FINDINGS: Recent reports continue to reflect the application of a variety of clinical, imaging or biochemical measurements, alone or in combination, to general Parkinson disease populations. Probably the most promising is the assay of alpha-synuclein in the diagnosis and evolution of Parkinson disease. At present, detection techniques are still being refined, but once accurate and reproducible assays are available, it will be important to define the relationship of these to early diagnosis and progression. Alpha-synuclein concentrations may also be modulated by certain disease-modifying agents in development and so may represent a measure of their efficacy. It has to be accepted that no single measure currently fulfils all the necessary criteria for a biomarker in Parkinson disease, but combinations of measures are more likely to deliver benefit. SUMMARY: The Parkinson disease biomarker field is approaching a stage when certain combinations of clinical, imaging and biochemical measures may identify a proportion of individuals at risk for developing the disease. However, their general applicability may be limited. Attention is now turning to stratification of Parkinson disease into certain at-risk groups defined by genotype. The application of multimodal screening to these populations may be more rewarding in the short term.

19 Review Targeting mitochondria for neuroprotection in Parkinson's disease. 2012

Schapira, Anthony Henry Vernon. ·Department of Clinical Neurosciences, UCL Institute of Neurology, London, United Kingdom. a.schapira@ucl.ac.uk ·Antioxid Redox Signal · Pubmed #22229791.

ABSTRACT: SIGNIFICANCE: Several genetic causes of familial Parkinson's disease (PD) have now been identified and include mutations of genes encoding mitochondrial proteins. Mitochondrial complex I toxins can induce dopaminergic cell death and produce a parkinsonian state. Importantly, defects of mitochondrial function have been identified in postmortem substantia nigra from pathologically proven cases of PD. RECENT ADVANCES: These observations provide compelling evidence to support the notion that mitochondria play an important role in the pathogenesis of PD. Thus, targeting mitochondrial function to delay or prevent neuronal cell death would represent a logical means to modify the course of this disease. Several attempts have already been made in this respect, and have been tested in clinical trial. CRITICAL ISSUES: To date, there is no unequivocal evidence for an effective intervention to slow the disease. However, several novel mitochondrial targets are now emerging, including the potential to manipulate the mitochondrial pool to maintain function via biogenesis and mitophagy. FUTURE DIRECTIONS: This development in drug targets needs to be supported by a parallel improvement in clinical trial design to be able to detect a neuroprotective or disease-modifying effect over a reasonable time scale.

20 Review Monoamine oxidase B inhibitors for the treatment of Parkinson's disease: a review of symptomatic and potential disease-modifying effects. 2011

Schapira, Anthony H V. ·Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK. ·CNS Drugs · Pubmed #22133327.

ABSTRACT: Parkinson's disease is a disorder characterized pathologically by progressive neurodegeneration of the dopaminergic cells of the nigrostriatal pathway. Although the resulting dopamine deficiency is the cause of the typical motor features of Parkinson's disease (bradykinesia, rigidity, tremor), additional non-motor symptoms appear at various timepoints and are the result of non-dopamine nerve degeneration. Monoamine oxidase B (MAO-B) inhibitors are used in the symptomatic treatment of Parkinson's disease as they increase synaptic dopamine by blocking its degradation. Two MAO-B inhibitors, selegiline and rasagiline, are currently licensed in Europe and North America for the symptomatic improvement of early Parkinson's disease and to reduce off-time in patients with more advanced Parkinson's disease and motor fluctuations related to levodopa. A third MAO-B inhibitor (safinamide), which also combines additional non-dopaminergic properties of potential benefit to Parkinson's disease, is currently under development in phase III clinical trials as adjuvant therapy to either a dopamine agonist or levodopa. MAO-B inhibitors have also been studied extensively for possible neuroprotective or disease-modifying actions. There is considerable laboratory evidence that MAO-B inhibitors do exert some neuroprotective properties, at least in the Parkinson's disease models currently available. However, these models have significant limitations and caution is required in assuming that such results may easily be extrapolated to clinical trials. Rasagiline 1 mg/day has been shown to provide improved motor control in terms of Unified Parkinson's Disease Rating Scale (UPDRS) score at 18 months in those patients with early disease who began the drug 9 months before a second group. There are a number of possible explanations for this effect that may include a disease-modifying action; however, the US FDA recently declined an application for the licence of rasagiline to be extended to cover disease modification.

21 Review Mitochondrial pathology in Parkinson's disease. 2011

Schapira, Anthony H V. ·Institute of Neurology, University College London, London, United Kingdom. a.schapira@medsch.ucl.ac.uk ·Mt Sinai J Med · Pubmed #22069211.

ABSTRACT: The last 25 years have witnessed remarkable advances in our understanding of the etiology and pathogenesis of Parkinson's disease. The ability to undertake detailed biochemical analyses of the Parkinson's disease postmortem brain enabled the identification of defects of mitochondrial and free-radical metabolism. The discovery of the first gene mutation for Parkinson's disease, in alpha-synuclein, ushered in the genetic era for the disease and the subsequent finding of several gene mutations causing parkinsonism, 15 at the time of writing. Technological advances both in sequencing technology and software analysis have allowed association studies of sufficiently large size accurately to describe genes conferring an increased risk for Parkinson's disease. What has been so surprising is the convergence of these 2 separate disciplines (biochemistry and genetics) in terms of reinforcing the importance of the same pathways (ie, mitochondrial dysfunction and free-radical metabolism). Other pathways are also important in pathogenesis, including protein turnover, inflammation, and post-translational modification, particularly protein phosphorylation and ubiquitination. However, even these additional pathways overlap with each other and with those of mitochondrial dysfunction and oxidative stress. This review explores these concepts with particular relevance to mitochondrial involvement.

22 Review Aetiopathogenesis of Parkinson's disease. 2011

Schapira, Anthony H V. ·University Department of Clinical Neurosciences, Institute of Neurology, University College London, Rowland Hill Street, London NW3 2PF, UK. a.schapira@medsch.ucl.ac.uk ·J Neurol · Pubmed #21560060.

ABSTRACT: Parkinson's disease (PD) is characterised both clinically and pathologically by features that distinguish it from other parkinsonian disorders including, for instance, multiple system atrophy and progressive supranuclear palsy. The aetiologies of PD includes both genetic and environmental influences. Several single gene causes of autosomal dominant and recessive PD have been described. Recent genome-wide association (GWA) studies have identified a number of risk alleles for PD. No specific environmental cause has been defined but several factors have been described which influence the risk for PD. Mitochondrial dysfunction, free radical mediated damage, inflammatory change and proteasomal dysfunction have been thought to play a role in PD pathogenesis. Autophagy is now recognised as an important component of the cell's mechanism for protein turnover and has relevance for PD. There is some convergence and overlap of pathogenetic pathways between environmental and genetic factors. The importance of identifying the molecular and biochemical events that lead to PD lies in the prospect that novel drug targets will emerge and that new compounds will be developed that slow the progression of the disease.

23 Review Safinamide in the treatment of Parkinson's disease. 2010

Schapira, Anthony H V. ·University College London, Institute of Neurology, Department of Clinical Neurosciences, Rowland Hill Street, London NW3 2PF, UK. a.schapira@medsch.ucl.ac.uk ·Expert Opin Pharmacother · Pubmed #20707760.

ABSTRACT: IMPORTANCE OF THE FIELD: Current therapy for Parkinson's disease (PD) is primarily directed at reversing the motor symptoms that are the consequence of dopamine deficiency and includes levodopa, dopamine agonists and monoamine oxidase (MAO) B inhibitors. New drugs offering both dopaminergic and non-dopaminergic actions could offer a significant advantage. AREAS COVERED IN THIS REVIEW: This review surveys the current treatment strategies for PD. Defining unmet needs and how a new compound - safinamide, which has both dopaminergic and non-dopaminergic actions - might address these. WHAT THE READER WILL GAIN: The reader will gain an understanding of safinamide and its mechanisms of action, including reversible MAOB inhibition and reduced dopamine reuptake with antiglutamatergic effects, and how it may potentially provide improvement of PD motor symptoms with an antidyskinetic effect through its effect on glutamate release. The clinical trial profile of safinamide is reviewed. Early results are promising in terms of improved motor function and reduced 'OFF' time. Additional Phase III trials are now in progress for this adjunctive indication. Finally, the reader will understand the potential role for safinamide in the selection and sequencing of drugs for PD. TAKE HOME MESSAGE: safinamide combines both dopaminergic and non-dopaminergic actions that may add a new dimension to PD treatment options as an adjunct to current drugs. Its efficacy is under active evaluation in Phase III clinical trials.

24 Review Missing pieces in the Parkinson's disease puzzle. 2010

Obeso, Jose A / Rodriguez-Oroz, Maria C / Goetz, Christopher G / Marin, Concepcion / Kordower, Jeffrey H / Rodriguez, Manuel / Hirsch, Etienne C / Farrer, Matthew / Schapira, Anthony H V / Halliday, Glenda. ·Department of Neurology, Clínica Universitaria and Medical School of Navarra, Neuroscience Centre, Center for Applied Medical Research, Pamplona, Spain. obeso@unav.es ·Nat Med · Pubmed #20495568.

ABSTRACT: Parkinson's disease is a neurodegenerative process characterized by numerous motor and nonmotor clinical manifestations for which effective, mechanism-based treatments remain elusive. Here we discuss a series of critical issues that we think researchers need to address to stand a better chance of solving the different challenges posed by this pathology.

25 Review Molecular and clinical prodrome of Parkinson disease: implications for treatment. 2010

Schapira, Anthony H V / Tolosa, Eduardo. ·Department of Clinical Neurosciences, Institute of Neurology, University College Medical School, Rowland Hill Street, London NW3 2PF, UK. a.schapira@medsch.ucl.ac.uk ·Nat Rev Neurol · Pubmed #20479780.

ABSTRACT: The development of interventions to slow or prevent progression represents an important aim for current research into Parkinson disease (PD). General agreement prevails that success in this endeavor will depend on a clearer understanding of etiology and pathogenesis, and several important advances have recently been made, particularly in defining the genetic causes of PD. Studies of the biochemical consequences of the mutations that cause familial PD, and postmortem brain studies of idiopathic, sporadic PD, have highlighted mitochondrial dysfunction, oxidative stress, and protein metabolism by the ubiquitin-proteasomal and autophagy systems as being central to pathogenesis. In parallel with advances in etiopathogenesis, a clearer perception has developed of the clinical prodrome of PD, offering an opportunity to identify individuals who are at risk of PD, as well as those in the earliest clinical phase of the disease that might even precede the onset of motor symptoms. These populations are potentially the most suitable in which to test new protective therapies, and to study potential peripheral markers of disease progression. The awareness of the early symptomatic period of PD also raises the possibility of providing treatments that not only improve motor function but might also favorably modify outcome.

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