Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Parkinson Disease: HELP
Articles from Cambridgeshire
Based on 267 articles published since 2008
||||

These are the 267 published articles about Parkinson Disease that originated from Cambridgeshire during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11
1 Editorial Taking the 'Disease' out of 'Parkinson's': has the disease had its day? 2019

Worth, Paul F. ·Addenbrooke's Hospital, Cambridge CB2 0QQ, UK paul.worth@addenbrookes.nhs.uk. ·Pract Neurol · Pubmed #30463982.

ABSTRACT: -- No abstract --

2 Editorial Stem cell therapies for Parkinson's disease: are trials just around the corner? 2014

Drouin-Ouellet, Janelle / Barker, Roger A. ·John van Geest Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 0PY, UK. ·Regen Med · Pubmed #25372072.

ABSTRACT: -- No abstract --

3 Editorial VPS35 Parkinson mutation impairs autophagy via WASH. 2014

Zavodszky, Eszter / Seaman, Matthew N J / Rubinsztein, David C. ·Department of Medical Genetics; Cambridge Institute for Medical Research; University of Cambridge; Wellcome Trust/MRC Building; Addenbrooke's Hospital; Cambridge UK. · Department of Clinical Biochemistry; Cambridge Institute for Medical Research; University of Cambridge; Wellcome Trust/MRC Building; Addenbrooke's Hospital; Cambridge UK. ·Cell Cycle · Pubmed #24963965.

ABSTRACT: -- No abstract --

4 Review Living in Promiscuity: The Multiple Partners of Alpha-Synuclein at the Synapse in Physiology and Pathology. 2019

Longhena, Francesca / Faustini, Gaia / Spillantini, Maria Grazia / Bellucci, Arianna. ·Division of Pharmacology, Department of molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. f.longhena@unibs.it. · Division of Pharmacology, Department of molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. g.faustini004@unibs.it. · Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0AH, UK. mgs11@cam.ac.uk. · Division of Pharmacology, Department of molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. arianna.bellucci@unibs.it. · Laboratory for Preventive and Personalized Medicine, Department of molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy. arianna.bellucci@unibs.it. ·Int J Mol Sci · Pubmed #30609739.

ABSTRACT: Alpha-synuclein (α-syn) is a small protein that, in neurons, localizes predominantly to presynaptic terminals. Due to elevated conformational plasticity, which can be affected by environmental factors, in addition to undergoing disorder-to-order transition upon interaction with different interactants, α-syn is counted among the intrinsically disordered proteins (IDPs) family. As with many other IDPs, α-syn is considered a hub protein. This function is particularly relevant at synaptic sites, where α-syn is abundant and interacts with many partners, such as monoamine transporters, cytoskeletal components, lipid membranes, chaperones and synaptic vesicles (SV)-associated proteins. These protein⁻protein and protein⁻lipid membrane interactions are crucial for synaptic functional homeostasis, and alterations in α-syn can cause disruption of this complex network, and thus a failure of the synaptic machinery. Alterations of the synaptic environment or post-translational modification of α-syn can induce its misfolding, resulting in the formation of oligomers or fibrillary aggregates. These α-syn species are thought to play a pathological role in neurodegenerative disorders with α-syn deposits such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), which are referred to as synucleinopathies. Here, we aim at revising the complex and promiscuous role of α-syn at synaptic terminals in order to decipher whether α-syn molecular interactants may influence its conformational state, contributing to its aggregation, or whether they are just affected by it.

5 Review Regenerative Therapies for Parkinson's Disease: An Update. 2018

Stoker, Thomas B / Barker, Roger A. ·John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. tbs26@cam.ac.uk. · Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK. tbs26@cam.ac.uk. · John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK. · Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK. ·BioDrugs · Pubmed #30027398.

ABSTRACT: Parkinson's disease is the second most common neurodegenerative disorder. It is characterised by a typical movement disorder that occurs in part because of the selective degeneration of the dopaminergic neurons of the substantia nigra pars compacta. Current treatment for the motor disorder of Parkinson's disease consists of dopaminergic medications, but these come with significant adverse effects, themselves an important part of the clinical course of Parkinson's disease, particularly in advanced stages. Therefore, treatment is needed that can restore dopaminergic tone in the striatum in a physiological and targeted manner to avert these side effects. A number of potential regenerative treatments have been developed with a view to achieving this. Following decades of optimisation and development of stem-cell-based treatments and viral gene delivery, clinical trials are on the horizon. For these treatments to be widely useful, they must be clinically effective, cost efficient and safe, and a number of practical aspects regarding storage and delivery of treatment must be optimised. Many barriers have been overcome, and the field of regenerative medicine for Parkinson's disease is now increasingly focussed on how these treatments will be delivered, demonstrating the significant progress that has been made and the optimism surrounding these approaches.

6 Review Exploring autophagy with Gene Ontology. 2018

Denny, Paul / Feuermann, Marc / Hill, David P / Lovering, Ruth C / Plun-Favreau, Helene / Roncaglia, Paola. ·a Functional Gene Annotation , Institute of Cardiovascular Science, University College London , London , UK. · b SIB Swiss Institute of Bioinformatics , Geneva , Switzerland. · c The Jackson Laboratory , Bar Harbor , ME , USA. · f The Gene Ontology Consortium. · d Department of Molecular Neuroscience , UCL Institute of Neurology , London , UK. · e European Bioinformatics Institute (EMBL-EBI) , European Molecular Biology Laboratory, Wellcome Genome Campus , Hinxton , Cambridge , UK. ·Autophagy · Pubmed #29455577.

ABSTRACT: Autophagy is a fundamental cellular process that is well conserved among eukaryotes. It is one of the strategies that cells use to catabolize substances in a controlled way. Autophagy is used for recycling cellular components, responding to cellular stresses and ridding cells of foreign material. Perturbations in autophagy have been implicated in a number of pathological conditions such as neurodegeneration, cardiac disease and cancer. The growing knowledge about autophagic mechanisms needs to be collected in a computable and shareable format to allow its use in data representation and interpretation. The Gene Ontology (GO) is a freely available resource that describes how and where gene products function in biological systems. It consists of 3 interrelated structured vocabularies that outline what gene products do at the biochemical level, where they act in a cell and the overall biological objectives to which their actions contribute. It also consists of 'annotations' that associate gene products with the terms. Here we describe how we represent autophagy in GO, how we create and define terms relevant to autophagy researchers and how we interrelate those terms to generate a coherent view of the process, therefore allowing an interoperable description of its biological aspects. We also describe how annotation of gene products with GO terms improves data analysis and interpretation, hence bringing a significant benefit to this field of study.

7 Review Autophagy impairment in Parkinson's disease. 2017

Karabiyik, Cansu / Lee, Min Jae / Rubinsztein, David C. ·Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, U.K. · Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Korea dcr1000@cam.ac.uk minjlee@snu.ac.kr. · Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, U.K. dcr1000@cam.ac.uk minjlee@snu.ac.kr. · UK Dementia Research Institute, Cambridge Biomedical Campus, Cambridge Biomedical Campus, Hills Road, Cambridge, U.K. ·Essays Biochem · Pubmed #29233880.

ABSTRACT: Parkinson's disease (PD) is a debilitating movement disorder typically associated with the accumulation of intracytoplasmic aggregate prone protein deposits. Over recent years, increasing evidence has led to the suggestion that the mutations underlying certain forms of PD impair autophagy. Autophagy is a degradative pathway that delivers cytoplasmic content to lysosomes for degradation and represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Autophagy up-regulation is a promising therapeutic strategy that is being explored for its potential to protect cells against the toxicity of aggregate-prone proteins in neurodegenerative diseases. Here, we describe how the mutations in different subtypes of PD can affect different stages of autophagy.

8 Review Hip fractures and Parkinson's disease: A case series. 2017

Coomber, Ross / Alshameeri, Zeiad / Masia, Antonio Francesco / Mela, Federico / Parker, Martyn J. ·Peterborough and Stamford Hospital NHS Foundation Trust, Department of Orthopaedics, Peterborough City Hospital, CBU PO Box 211, Core C, Bretton Gate, Peterborough PE3 9GZ UK. Electronic address: rosscoomber@hotmail.com. · Peterborough and Stamford Hospital NHS Foundation Trust, Department of Orthopaedics, Peterborough City Hospital, CBU PO Box 211, Core C, Bretton Gate, Peterborough PE3 9GZ UK. Electronic address: zeiad@doctors.org.uk. · Department of Surgical, Microsurgical and Medical Sciences, Institute of Orthopaedic Clinic, Univeristy of Sassari, Sassari, Italy. Electronic address: Francesco.masia@icloud.com. · Department of Surgical, Microsurgical and Medical Sciences, Institute of Orthopaedic Clinic, Univeristy of Sassari, Sassari, Italy. Electronic address: federicomela86@hotmail.it. · Peterborough and Stamford Hospital NHS Foundation Trust, Department of Orthopaedics, Peterborough City Hospital, CBU PO Box 211, Core C, Bretton Gate, Peterborough PE3 9GZ UK. Electronic address: Martyn.Parker@pbh-tr.nhs.uk. ·Injury · Pubmed #28985911.

ABSTRACT: There are no specific guidelines for treating Parkinson's disease patients who present with a hip fracture. Here we present a large cohort of patients with Parkinson's disease who suffered hip fractures. Our aim was to assess for differences between a Parkinson's disease population and a non-Parkinson's disease population with hip fractures and make recommendations on management guidelines. We performed a comprehensive analysis of prospectively collected data on all patients with hip fracture who were admitted into our department over a period of 29 years. In total 9225 patients with hip fractures were included in this study, 452 (4.9%) patients had Parkinson's disease. The mobility scores were worse pre- and post-operatively in the Parkinson's group as were mini-mental scores and ASA grade. Post-operative complications were similar between the two groups, with no difference in dislocation rate or wound complications. However, other outcomes including mobility and mortality rate at 1year were worse in the Parkinson's group. These patients also had a longer hospital stay and were more likely to be immobile and discharged to an institution. We recommend that Parkinson's disease patients should be assessed more thoroughly in the peri-operative period and arrangement for rehab and discharge planning should commence as soon as possible following admission. The consent process should reflect longer hospital stays, worse mobility, higher mortality and increased likelihood of discharge to institution but concern over increased complications, specifically dislocation was not evident in our data.

9 Review Cognition in Parkinson's Disease. 2017

O'Callaghan, Claire / Lewis, Simon J G. ·University of Cambridge, Cambridge, United Kingdom; Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia. Electronic address: co365@cam.ac.uk. · Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia. ·Int Rev Neurobiol · Pubmed #28802933.

ABSTRACT: Cognitive decline is now recognized as a common nonmotor symptom of Parkinson's disease, and it has been the subject of increasing research in recent decades. Cognitive deficits in Parkinson's disease can be distinguished as dopaminergically mediated executive dysfunction seen in the milder stages vs a global dementia syndrome that can occur with disease progression. The neural basis of these deficits has been explored from the perspective of multimodal imaging techniques to measure the structural, functional, and metabolic correlates of cognitive decline in Parkinson's disease. Increasingly, changes in neurotransmitter systems beyond dopamine, including the noradrenergic, serotonergic, and cholinergic systems, are being recognized for their contribution to cognitive decline. The impact of certain genetic variations on cognitive function has also been established, including links between cognitive decline and polymorphisms affecting COMT, MAPT, APOE, and GBA genotypes. Although therapeutic options for cognitive decline are still far less established than for motor systems, both pharmacological and nonpharmacological strategies are continuing to develop.

10 Review Respiratory dysfunction in Parkinson's disease. 2017

Torsney, K M / Forsyth, D. ·D Forsyth, Department of Medicine for, the Elderly, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. Email: duncan.forsyth@addenbrookes.nhs.uk. ·J R Coll Physicians Edinb · Pubmed #28569280.

ABSTRACT: Respiratory dysfunction has been associated with Parkinson's disease since it was first described in 1817. The respiratory symptoms observed in Parkinson's disease patients vary greatly. Most patients remain asymptomatic, whereas others present with acute shortness of breath and even stridor. In August 2016, an electronic literature search was conducted using PubMed and Google Scholar. Results were screened and studies reporting on respiratory dysfunction associated with Parkinson's disease were included. Respiratory dysfunction is due to a combination of factors including restrictive changes, upper airway obstruction, abnormal ventilatory drive and response to medications. Much debate surrounds the mechanism underlying respiratory dysfunction in Parkinson's disease, its prevalence and the effect of levodopa on respiration. It is clear from this review that larger studies, comparing patients of similar disease duration and severity using the same pulmonary function parameters, are required to provide a better understanding of the pathophysiology underlying respiratory dysfunction in Parkinson's disease.

11 Review Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. 2017

Chiti, Fabrizio / Dobson, Christopher M. ·Department of Experimental and Clinical Biomedical Sciences "Mario Serio," Section of Biochemistry, Università di Firenze, 50134 Firenze, Italy; email: fabrizio.chiti@unifi.it. · Department of Chemistry, Centre for Misfolding Diseases, University of Cambridge, Cambridge CB2 1EW, United Kingdom; email: cmd44@cam.ac.uk. ·Annu Rev Biochem · Pubmed #28498720.

ABSTRACT: Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.

12 Review Development of LRRK2 Inhibitors for the Treatment of Parkinson's Disease. 2017

Christensen, K V / Smith, G P / Williamson, D S. ·Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark. · Vernalis (R&D) Ltd, Cambridge, United Kingdom. ·Prog Med Chem · Pubmed #28314412.

ABSTRACT: Linkage and genome-wide association studies have identified a genetic risk locus for late-onset Parkinson's disease in chromosome 12, originally identified as PARK6. The causative gene was identified to code for a large multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment. Although LRRK2 has so far not been crystallised, the use of homology modelling and crystallographic surrogates has allowed the optimisation of chemical structures such that compounds of high selectivity with good brain penetration and appropriate pharmacokinetic properties are now available for understanding the biology of LRRK2 in vitro and in vivo. This chapter reviews LRRK2 biology, the structural biology of LRRK2 and gives an overview of inhibitors of LRRK2.

13 Review The Synucleinopathies: Twenty Years On. 2017

Goedert, Michel / Jakes, Ross / Spillantini, Maria Grazia. ·MRC Laboratory of Molecular Biology, Cambridge, UK. · Department of Clinical Neurosciences, Clifford Allbutt Building, Cambridge, AH, UK. ·J Parkinsons Dis · Pubmed #28282814.

ABSTRACT: In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.

14 Review Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update. 2017

Voon, Valerie / Napier, T Celeste / Frank, Michael J / Sgambato-Faure, Veronique / Grace, Anthony A / Rodriguez-Oroz, Maria / Obeso, Jose / Bezard, Erwan / Fernagut, Pierre-Olivier. ·Department of Psychiatry and Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, UK; Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK. Electronic address: vv247@cam.ac.uk. · Departments of Pharmacology and Psychiatry, Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, IL, USA. · Department of Cognitive, Linguistic and Psychological Sciences and Department of Psychiatry and Human Behavior, Brown Institute for Brain Science, Providence, RI, USA. · Institut des Sciences Cognitives Marc Jeannerod, CNRS, Bron, France; Université Claude Bernard Lyon 1, Villeurbanne, France. · Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA. · Biodonostia Health Research Institute, University Hospital Donostia, and Basque Center on Cognition, Brain and Language, San Sebastián, Spain; Ikerbasque-Basque Foundation for Science, Bilbao, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto Carlos III, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto Carlos III, Spain; HM Centro Integral de Neurociencias, HM Puerta del Sur, Mostoles and Centro de Estudios Universitarios-San Pablo University, Madrid, Spain. · Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux, France; Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, Bordeaux, France. ·Lancet Neurol · Pubmed #28229895.

ABSTRACT: Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.

15 Review PINK1/Parkin mitophagy and neurodegeneration-what do we really know in vivo? 2017

Whitworth, Alexander J / Pallanck, Leo J. ·MRC Mitochondrial Biology Unit, Cambridge Biomedical Campus, Hills Road, Cambridge, United Kingdom. Electronic address: a.whitworth@mrc-mbu.cam.ac. · Department of Genome Sciences, University of Washington, Seattle, WA, United States. Electronic address: pallanck@uw.edu. ·Curr Opin Genet Dev · Pubmed #28213158.

ABSTRACT: Mitochondria are essential organelles that provide cellular energy and buffer cytoplasmic calcium. At the same time they produce damaging reactive oxygen species and sequester pro-apoptotic factors. Hence, eukaryotes have evolved exquisite homeostatic processes that maintain mitochondrial integrity, or ultimately remove damaged organelles. This subject has garnered intense interest recently following the discovery that two Parkinson's disease genes, PINK1 and parkin, regulate mitochondrial degradation (mitophagy). The molecular details of PINK1/Parkin-induced mitophagy are emerging but much of our insight derives from work using cultured cells and potent mitochondrial toxins, raising questions about the physiological significance of these findings. Here we review the evidence supporting PINK1/Parkin mitophagy in vivo and its causative role in neurodegeneration, and outline outstanding questions for future investigations.

16 Review The Amyloid Phenomenon and Its Links with Human Disease. 2017

Dobson, Christopher M. ·Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom. ·Cold Spring Harb Perspect Biol · Pubmed #28062560.

ABSTRACT: The ability of normally soluble proteins to convert into amyloid fibrils is now recognized to be a generic phenomenon. The overall cross-β architecture of the core elements of such structures is closely similar for different amino acid sequences, as this architecture is dominated by interactions associated with the common polypeptide main chain. In contrast, the multiplicity of complex and intricate structures of the functional states of proteins is dictated by specific interactions involving the variable side chains, the sequence of which is unique to a given protein. Nevertheless, the side chains dictate important aspects of the amyloid structure, including the regions of the sequence that form the core elements of the fibrils and the kinetics and mechanism of the conversion process. The formation of the amyloid state of proteins is of particular importance in the context of a range of medical disorders that include Alzheimer's and Parkinson's diseases and type 2 diabetes. These disorders are becoming increasingly common in the modern world, primarily as a consequence of increasing life spans and changing lifestyles, and now affect some 500 million people worldwide. This review describes recent progress in our understanding of the molecular origins of these conditions and discusses emerging ideas for new and rational therapeutic strategies by which to combat their onset and progression.

17 Review Mechanisms of Parkinson's Disease: Lessons from Drosophila. 2017

Hewitt, V L / Whitworth, A J. ·Medical Research Council Mitochondrial Biology Unit, Cambridge, United Kingdom. · Medical Research Council Mitochondrial Biology Unit, Cambridge, United Kingdom. Electronic address: a.whitworth@mrc-mbu.cam.ac.uk. ·Curr Top Dev Biol · Pubmed #28057299.

ABSTRACT: The power of Drosophila genetics has attracted attention in tackling important biomedical challenges such as the understanding and prevention of neurodegenerative diseases. Parkinson's disease (PD) is the most common neurodegenerative movement disorder which results from the relentless degeneration of midbrain dopaminergic neurons. Over the past two decades tremendous advances have been made in identifying genes responsible for inherited forms of PD. The ease of genetic manipulation in Drosophila has spurred the development of numerous models of PD, including expression of human genes carrying pathogenic mutations or the targeted mutation of conserved orthologs. The genetic and cellular analysis of these models is beginning to reveal fundamental insights into the pathogenic mechanisms. Numerous pathways and processes are disrupted in these models but some common themes are emerging. These often implicate aberrant synaptic function, protein aggregation, autophagy, oxidative stress, and mitochondrial dysfunction. Moreover, an impressive list of small molecule compounds have been identified as effective in reversing pathogenic phenotypes, paving the way to explore these for therapeutic interventions.

18 Review The Transcellular Propagation and Intracellular Trafficking of α-Synuclein. 2017

Tofaris, George K / Goedert, Michel / Spillantini, Maria Grazia. ·Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. · MRC Laboratory of Molecular Biology, Cambridge, UK. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. ·Cold Spring Harb Perspect Med · Pubmed #27920026.

ABSTRACT: Parkinson's disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfolded α-synuclein conformers, which can template the aggregation of soluble monomers and lead to cellular dysfunction, at least partly by interfering with membrane fusion events at synaptic terminals. Here, we discuss the transcellular propagation and intracellular trafficking of α-synuclein and posit that endosomal processing could be a point of convergence between these two routes. Understanding these events will clarify the therapeutic potential of enzymes that regulate protein trafficking and degradation in synucleinopathies.

19 Review Neuroendocrine abnormalities in Parkinson's disease. 2017

De Pablo-Fernández, Eduardo / Breen, David P / Bouloux, Pierre M / Barker, Roger A / Foltynie, Thomas / Warner, Thomas T. ·Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK. · Queen Square Brain Bank for Neurological Disorders, UCL Institute of Neurology, London, UK. · John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK. · Centre for Neuroendocrinology, Royal Free Campus, UCL Institute of Neurology, London, UK. · Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK. ·J Neurol Neurosurg Psychiatry · Pubmed #27799297.

ABSTRACT: Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.

20 Review Structure and Function of Fbxo7/PARK15 in Parkinson's Disease. 2017

Randle, Suzanne J / Laman, Heike. ·Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom. ·Curr Protein Pept Sci · Pubmed #26965690.

ABSTRACT: Fbxo7/PARK15 has well-defined roles, acting as part of a Skp1-Cul1-F box protein (SCF)- type E3 ubiquitin ligase and also having SCF-independent activities. Mutations within FBXO7 have been found to cause an early-onset Parkinson's disease, and these are found within or near to its functional domains, including its F-box domain (FBD), its proline rich region (PRR), and its ubiquitinlike domain (Ubl). We highlight recent advances in our understanding of Fbxo7 function in Parkinson's disease, with respect to these mutations and where they occur in the Fbxo7 protein. We hypothesize that many of Fbxo7 functions contribute to its role in PD pathogenesis.

21 Review The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review. 2016

Wen, Ke-Xin / Miliç, Jelena / El-Khodor, Bassem / Dhana, Klodian / Nano, Jana / Pulido, Tammy / Kraja, Bledar / Zaciragic, Asija / Bramer, Wichor M / Troup, John / Chowdhury, Rajiv / Ikram, M Arfam / Dehghan, Abbas / Muka, Taulant / Franco, Oscar H. ·Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands. · Research and Development, Metagenics, Inc, United States of America. · Department of Biomedical Sciences, Faculty of Medicine, University of Medicine, Tirana, Albania. · University Clinic of Gastrohepatology, University Hospital Center Mother Teresa, Tirana, Albania. · Medical Library, Erasmus MC, Rotterdam, The Netherlands. · Department of Public Health & Primary Care, Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB1 8RN, United Kingdom. ·PLoS One · Pubmed #27973581.

ABSTRACT: IMPORTANCE: Epigenetic modifications of the genome, such as DNA methylation and histone modifications, have been reported to play a role in neurodegenerative diseases (ND) such as Alzheimer's disease (AD) and Parkinson's disease (PD). OBJECTIVE: To systematically review studies investigating epigenetic marks in AD or PD. METHODS: Eleven bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, Scopus, PubMed, Cinahl (EBSCOhost), Cochrane Central, ProQuest, Lilacs, Scielo and Google Scholar) were searched until July 11th 2016 to identify relevant articles. We included all randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined associations between epigenetic marks and ND. Two independent reviewers, with a third reviewer available for disagreements, performed the abstract and full text selection. Data was extracted using a pre-designed data collection form. RESULTS: Of 6,927 searched references, 73 unique case-control studies met our inclusion criteria. Overall, 11,453 individuals were included in this systematic review (2,640 AD and 2,368 PD outcomes). There was no consistent association between global DNA methylation pattern and any ND. Studies reported epigenetic regulation of 31 genes (including cell communication, apoptosis, and neurogenesis genes in blood and brain tissue) in relation to AD and PD. Methylation at the BDNF, SORBS3 and APP genes in AD were the most consistently reported associations. Methylation of α-synuclein gene (SNCA) was also found to be associated with PD. Seven studies reported histone protein alterations in AD and PD. CONCLUSION: Many studies have investigated epigenetics and ND. Further research should include larger cohort or longitudinal studies, in order to identify clinically significant epigenetic changes. Identifying relevant epigenetic changes could lead to interventional strategies in ND.

22 Review Diffusion alterations associated with Parkinson's disease symptomatology: A review of the literature. 2016

Hall, Julie M / Ehgoetz Martens, Kaylena A / Walton, Courtney C / O'Callaghan, Claire / Keller, Peter E / Lewis, Simon J G / Moustafa, Ahmed A. ·Brain and Mind Centre, University of Sydney, Sydney, Australia; School of Social Sciences and Psychology, Western Sydney University, Sydney, Australia. · Brain and Mind Centre, University of Sydney, Sydney, Australia. · Brain and Mind Centre, University of Sydney, Sydney, Australia; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, United Kingdom; Department of Psychology, University of Cambridge, Cambridge, UK. · MARCS Institute, Western Sydney University, Sydney, Australia. · Brain and Mind Centre, University of Sydney, Sydney, Australia. Electronic address: simonl@med.usyd.edu.au. · School of Social Sciences and Psychology, Western Sydney University, Sydney, Australia; MARCS Institute, Western Sydney University, Sydney, Australia. ·Parkinsonism Relat Disord · Pubmed #27765426.

ABSTRACT: Parkinson's disease (PD) is a heterogeneous neurological disorder with a variety of motor and non-motor symptoms. The underlying mechanisms of these symptoms are not fully understood. An increased interest in structural connectivity analyses using diffusion tensor imaging (DTI) in PD has led to an expansion of our understanding of the impact of abnormalities in diffusivity on phenotype. This review outlines the contribution of these abnormalities to symptoms of PD including bradykinesia, tremor and non-tremor phenotypes, freezing of gait, cognitive impairment, mood, sleep disturbances, visual hallucinations and olfactory dysfunction. Studies have shown that impairments in cognitive functioning are related to diffusion abnormalities in frontal and parietal regions, as well as in the corpus callosum and major fibres connecting midbrain and subcortical structures with the neocortex. However, the impact of diffusion alterations on motor, mood and other symptoms of PD are less well understood. The findings presented here highlight the challenges faced and the potential areas of future research avenues where DTI may be beneficial. Larger cohort studies and standardized imaging protocols are required to investigate current promising preliminary findings.

23 Review 'Under pressure': is there a link between orthostatic hypotension and cognitive impairment in α-synucleinopathies? 2016

Udow, Sean J / Robertson, Andrew D / MacIntosh, Bradley J / Espay, Alberto J / Rowe, James B / Lang, Anthony E / Masellis, Mario. ·Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · L.C. Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada. · Hurvitz Brain Sciences Program, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. · Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA. · Cognition and Brain Sciences Unit, Medical Research Council, Cambridge, UK. · Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. · Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. · Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. · Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. ·J Neurol Neurosurg Psychiatry · Pubmed #27613160.

ABSTRACT: Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterised by abnormal neuroglial α-synuclein accumulation. These α-synucleinopathies have in common parkinsonism and non-motor features including orthostatic hypotension (OH) and cognitive impairment. However, the nature of the relationship between OH and cognitive impairment is unclear. We therefore systematically reviewed the literature for evidence of an association between OH and cognitive impairment in α-synucleinopathies and discuss possible mechanisms and implications of this relationship. Abstracts from 313 original research articles were surveyed, and a total of 132 articles were considered for this review. Articles were stratified as: 'direct-evidence studies' based on the direct assessment for a relationship between OH and cognitive impairment in α-synucleinopathies, and 'indirect-evidence studies' based on an association being referred to as a secondary outcome. Ten 'direct-evidence papers' were identified, seven of which reported a positive association between OH and cognitive impairment, while seven of 12 'indirect-evidence papers' similarly did as well. The papers that reported no association between OH and cognitive impairment used less sensitive measures of cognition. A relationship between OH and cognitive impairment in patients with α-synucleinopathies exists, but the underlying mechanisms remain unclear. Three hypotheses are proposed: (1) OH and cognitive impairment occur concurrently due to diffuse brain and peripheral deposition of α-synuclein, (2) OH-mediated cerebral hypoperfusion impairs cognition and (3) the two act synergistically to accelerate cognitive decline. Longitudinal neuroimaging studies and clinical trials may help clarify the nature of this relationship.

24 Review Prodromal Parkinson's disease as defined per MDS research criteria in the general elderly community. 2016

Mahlknecht, Philipp / Gasperi, Arno / Willeit, Peter / Kiechl, Stefan / Stockner, Heike / Willeit, Johann / Rungger, Gregorio / Sawires, Martin / Nocker, Michael / Rastner, Verena / Mair, Katherina J / Hotter, Anna / Poewe, Werner / Seppi, Klaus. ·Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, United Kingdom. · Department of Neurology, Hospital of Bruneck, Bruneck, Italy. · King's British Heart Foundation Centre, King's College London, London, United Kingdom. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. Werner.Poewe@i-med.ac.at. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. Klaus.Seppi@tirol-kliniken.at. ·Mov Disord · Pubmed #27273736.

ABSTRACT: BACKGROUND: Recently, the International Parkinson and Movement Disorder Society has defined research criteria for prodromal Parkinson's disease (PD), but to date their predictive value has not yet been tested in population-based cohorts. METHODS: We retrospectively applied these criteria to the longitudinal Bruneck Study cohort aged 55-94 years using recorded data on all included risk and prodromal markers that are quick and easily assessable. RESULTS: After excluding participants with idiopathic PD or secondary parkinsonism, prevalence of probable prodromal PD in the remaining 539 participants was 2.2% (95% confidence interval, 1.2%-3.9%). Of 488 participants followed up over 5 years, 11 developed incident PD. Sensitivity of "probable prodromal PD" status for incident PD was 54.6% (95% confidence interval, 28.0%-78.8%), specificity was 99.2% (97.8%-99.8%), positive predictive value was 60.0% (31.2%-83.3%), and negative predictive value was 99.0% (97.5%-99.6%). CONCLUSIONS: Our findings suggest that the new research criteria for prodromal PD are a promising tool to identify cases of incident PD over 5 years, arguing for their usefulness in defining target populations for disease-prevention trials. © 2016 International Parkinson and Movement Disorder Society.

25 Review Ubiquitin modifications. 2016

Swatek, Kirby N / Komander, David. ·Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. ·Cell Res · Pubmed #27012465.

ABSTRACT: Protein ubiquitination is a dynamic multifaceted post-translational modification involved in nearly all aspects of eukaryotic biology. Once attached to a substrate, the 76-amino acid protein ubiquitin is subjected to further modifications, creating a multitude of distinct signals with distinct cellular outcomes, referred to as the 'ubiquitin code'. Ubiquitin can be ubiquitinated on seven lysine (Lys) residues or on the N-terminus, leading to polyubiquitin chains that can encompass complex topologies. Alternatively or in addition, ubiquitin Lys residues can be modified by ubiquitin-like molecules (such as SUMO or NEDD8). Finally, ubiquitin can also be acetylated on Lys, or phosphorylated on Ser, Thr or Tyr residues, and each modification has the potential to dramatically alter the signaling outcome. While the number of distinctly modified ubiquitin species in cells is mind-boggling, much progress has been made to characterize the roles of distinct ubiquitin modifications, and many enzymes and receptors have been identified that create, recognize or remove these ubiquitin modifications. We here provide an overview of the various ubiquitin modifications present in cells, and highlight recent progress on ubiquitin chain biology. We then discuss the recent findings in the field of ubiquitin acetylation and phosphorylation, with a focus on Ser65-phosphorylation and its role in mitophagy and Parkin activation.

Next