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Parkinson Disease: HELP
Articles from South Africa
Based on 116 articles published since 2009

These are the 116 published articles about Parkinson Disease that originated from South Africa during 2009-2019.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Guideline Guideline for the treatment of Parkinson's disease. 2009

Carr, J / Kies, B / Fine, J / Anonymous220650. ·jcarr@sun.ac.za ·S Afr Med J · Pubmed #20128276.

ABSTRACT: -- No abstract --

2 Editorial A putative founder effect for Parkinson's disease in South African Afrikaners. 2014

Carr, Jonathan / van Coller, Riaan. ·Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa. jcarr@sun.ac.za. ·S Afr Med J · Pubmed #25214249.

ABSTRACT: -- No abstract --

3 Review The unresolved role of mitochondrial DNA in Parkinson's disease: An overview of published studies, their limitations, and future prospects. 2019

Müller-Nedebock, Amica C / Brennan, Rebecca R / Venter, Marianne / Pienaar, Ilse S / van der Westhuizen, Francois H / Elson, Joanna L / Ross, Owen A / Bardien, Soraya. ·Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa. · Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. · Human Metabolomics, North-West University, Potchefstroom, South Africa. · School of Life Sciences, University of Sussex, Falmer, BN1 9PH, United Kingdom; Centre for Neuroinflammation and Neurodegeneration, Imperial College London, London, United Kingdom. · Human Metabolomics, North-West University, Potchefstroom, South Africa; Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom. · Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA; School of Medicine and Medical Science, University College Dublin, Dublin, Ireland. · Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa. Electronic address: sbardien@sun.ac.za. ·Neurochem Int · Pubmed #31233840.

ABSTRACT: Parkinson's disease (PD), a progressive neurodegenerative disorder, has long been associated with mitochondrial dysfunction in both sporadic and familial forms of the disease. Mitochondria are crucial for maintaining cellular homeostasis, and their dysfunction is detrimental to dopaminergic neurons. These neurons are highly dependent on mitochondrial adenosine triphosphate (ATP) and degenerate in PD. Mitochondria contain their own genomes (mtDNA). The role of mtDNA has been investigated in PD on the premise that it encodes vital components of the ATP-generating oxidative phosphorylation (OXPHOS) complexes and accumulates somatic variation with age. However, the association between mtDNA variation and PD remains controversial. Herein, we provide an overview of previously published studies on the role of inherited as well as somatic (acquired) mtDNA changes in PD including point mutations, deletions and depletion. We outline limitations of previous investigations and the difficulties associated with studying mtDNA, which have left its role unresolved in the context of PD. Lastly, we highlight the potential for further research in this field and provide suggestions for future studies. Overall, the mitochondrial genome is indispensable for proper cellular function and its contribution to PD requires further, more extensive investigation.

4 Review Parkinson's disease in Nigeria: A review of published studies and recommendations for future research. 2019

Oluwole, Oluwafemi G / Kuivaniemi, Helena / Carr, Jonathan A / Ross, Owen A / Olaogun, Matthew O B / Bardien, Soraya / Komolafe, Morenikeji A. ·Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. · Division of Neurology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA. · Department of Medical Rehabilitation, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria. · Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. Electronic address: sbardien@sun.ac.za. · Neurology Unit, Department of Medicine, College of Health Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria. Electronic address: adeyoyin2001@yahoo.com. ·Parkinsonism Relat Disord · Pubmed #30573414.

ABSTRACT: Parkinson's disease (PD) affects 1-2% of individuals above 60 years amounting to over 7 million people worldwide. Thus, PD has become an important contributor to the neurological disease burden. Nigeria is the most populous country in Africa, and alarmingly, approximately 5.25 million Nigerians are above 65 years and are therefore at risk for developing PD. We carried out a critical review of published literature on PD in Nigeria to summarize the findings and to evaluate gaps in knowledge. Seven electronic databases were searched for studies published in English before 18th July 2018. Search terms were ["Parkinson's disease" OR "Parkinson disease" OR "parkinsonian disorders" OR "Parkinsonism"] AND "Nigeria". A total of 44 articles (including eight reviews) published since 1969 were identified and reviewed. Amongst the original research articles, most (23) were on PD symptoms or prevalence. There were only two studies on genetics and two on environmental factors. The estimated crude prevalence of PD in Nigeria was lower (10-249/100 000) compared to studies published in Europe (65.6-12 500/100 000). Our findings suggest that PD is under-diagnosed in Nigeria. Possible environmental risk factors identified include blacksmithing and well-water contaminated with trace metals. Given the rising numbers of the ageing population in Nigeria, more studies to evaluate the prevalence and causes of PD in this country are urgently needed. To this end, more funding, resources and a workforce of well-trained neurologists and scientists are essential to manage the impending health burden of PD and related disorders in this country.

5 Review Brain Dopamine Transmission in Health and Parkinson's Disease: Modulation of Synaptic Transmission and Plasticity Through Volume Transmission and Dopamine Heteroreceptors. 2018

Borroto-Escuela, Dasiel O / Perez De La Mora, Miguel / Manger, Paul / Narváez, Manuel / Beggiato, Sarah / Crespo-Ramírez, Minerva / Navarro, Gemma / Wydra, Karolina / Díaz-Cabiale, Zaida / Rivera, Alicia / Ferraro, Luca / Tanganelli, Sergio / Filip, Małgorzata / Franco, Rafael / Fuxe, Kjell. ·Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. · Section of Physiology, Department of Biomolecular Science, University of Urbino, Urbino, Italy. · Observatorio Cubano de Neurociencias, Grupo Bohío-Estudio, Yaguajay, Cuba. · Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico. · Faculty of Health Sciences, School of Anatomical Sciences, University of the Witwatersrand, Johannesburg, South Africa. · Facultad de Medicina, Instituto de Investigación Biomédica de Málaga, Málaga, Spain. · Department of Medical Sciences, University of Ferrara, Ferrara, Italy. · Department of Biochemistry and Molecular Biomedicine, Faculty of Biomedicine, University of Barcelona, Barcelona, Spain. · Laboratory of Drug Addiction Pharmacology, Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. · Department of Cell Biology, Faculty of Sciences, University of Málaga, Málaga, Spain. · Department of Life Sciences and Biotechnology (SVEB), University of Ferrara, Ferrara, Italy. · CiberNed: Centro de Investigación en Red Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain. ·Front Synaptic Neurosci · Pubmed #30042672.

ABSTRACT: This perspective article provides observations supporting the view that nigro-striatal dopamine neurons and meso-limbic dopamine neurons mainly communicate through short distance volume transmission in the um range with dopamine diffusing into extrasynaptic and synaptic regions of glutamate and GABA synapses. Based on this communication it is discussed how volume transmission modulates synaptic glutamate transmission onto the D1R modulated direct and D2R modulated indirect GABA pathways of the dorsal striatum. Each nigro-striatal dopamine neuron was first calculated to form large numbers of neostriatal DA nerve terminals and then found to give rise to dense axonal arborizations spread over the neostriatum, from which dopamine is released. These neurons can through DA volume transmission directly influence not only the striatal GABA projection neurons but all the striatal cell types in parallel. It includes the GABA nerve cells forming the island-/striosome GABA pathway to the nigral dopamine cells, the striatal cholinergic interneurons and the striatal GABA interneurons. The dopamine modulation of the different striatal nerve cell types involves the five dopamine receptor subtypes, D1R to D5R receptors, and their formation of multiple extrasynaptic and synaptic dopamine homo and heteroreceptor complexes. These features of the nigro-striatal dopamine neuron to modulate in parallel the activity of practically all the striatal nerve cell types in the dorsal striatum, through the dopamine receptor complexes allows us to understand its unique and crucial fine-tuning of movements, which is lost in Parkinson's disease. Integration of striatal dopamine signals with other transmitter systems in the striatum mainly takes place via the receptor-receptor interactions in dopamine heteroreceptor complexes. Such molecular events also participate in the integration of volume transmission and synaptic transmission. Dopamine modulation of the glutamate synapses on the dorsal striato-pallidal GABA pathway involves D2R heteroreceptor complexes such as D2R-NMDAR, A2AR-D2R, and NTSR1-D2R heteroreceptor complexes. The dopamine modulation of glutamate synapses on the striato-entopeduncular/nigral pathway takes place mainly via D1R heteroreceptor complexes such as D1R-NMDAR, A2R-D1R, and D1R-D3R heteroreceptor complexes. Dopamine modulation of the island/striosome compartment of the dorsal striatum projecting to the nigral dopamine cells involve D4R-MOR heteroreceptor complexes. All these receptor-receptor interactions have relevance for Parkinson's disease and its treatment.

6 Review Early Life Stress, Depression And Parkinson's Disease: A New Approach. 2018

Dallé, Ernest / Mabandla, Musa V. ·School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa. dumessherve@yahoo.fr. · School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa. ·Mol Brain · Pubmed #29551090.

ABSTRACT: This review aims to shed light on the relationship that involves exposure to early life stress, depression and Parkinson's disease (PD). A systematic literature search was conducted in Pubmed, MEDLINE, EBSCOHost and Google Scholar and relevant data were submitted to a meta-analysis . Early life stress may contribute to the development of depression and patients with depression are at risk of developing PD later in life. Depression is a common non-motor symptom preceding motor symptoms in PD. Stimulation of regions contiguous to the substantia nigra as well as dopamine (DA) agonists have been shown to be able to attenuate depression. Therefore, since PD causes depletion of dopaminergic neurons in the substantia nigra, depression, rather than being just a simple mood disorder, may be part of the pathophysiological process that leads to PD. It is plausible that the mesocortical and mesolimbic dopaminergic pathways that mediate mood, emotion, and/or cognitive function may also play a key role in depression associated with PD. Here, we propose that a medication designed to address a deficiency in serotonin is more likely to influence motor symptoms of PD associated with depression. This review highlights the effects of an antidepressant, Fluvoxamine maleate, in an animal model that combines depressive-like symptoms and Parkinsonism.

7 Review A review of genome-wide transcriptomics studies in Parkinson's disease. 2018

Borrageiro, Genevie / Haylett, William / Seedat, Soraya / Kuivaniemi, Helena / Bardien, Soraya. ·Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 241, Cape Town, South Africa. · Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. ·Eur J Neurosci · Pubmed #29068110.

ABSTRACT: Parkinson's disease (PD) is a progressive and incurable neurodegenerative disorder. Although numerous genetic and environmental factors have been linked to the aetiology of PD the underlying pathobiology remains poorly understood, hampering the development of improved therapies. Transcriptomics has the potential to reveal significant insights into disease processes. In this review, we focused on published transcriptomics studies on PD with the aim of summarizing studies and identifying common biological pathways. A total of 96 articles were identified as follows: 12 meta-analyses, 21 re-analyses of existing data and 63 original studies. Of the 63 original studies, 33 were performed on brain tissue, 26 on blood, three on cerebrospinal fluid and one on skin. In the brain studies, altered pathways identified included those involved in dopamine metabolism, mitochondrial function, oxidative stress, protein degradation, neuroinflammation, vesicular transport and synaptic transmission. Studies on blood samples revealed alterations in pathways involved in immune function, inflammation, RNA processing, protein chaperones, mitochondrial function and programmed cell death. Limitations of these studies include small sample sizes (generally <40 cases/40 controls) and the application of widely varying statistical analysis and parameters. Only eight studies used the RNA-Seq technique. This review highlights the need for harmonization of transcriptomic approaches and the statistical analyses, and for the data to be deposited into publicly available databases in a standardized format for meta-analyses. Notably, the concordance of several pathways such as mitochondrial function, protein degradation and inflammation, identified in both blood and brain tissues, suggests that the disease process is systemic and not restricted to neurological tissues.

8 Review Mitochondrial Dynamics and Proteins Related to Neurodegenerative Diseases. 2018

Alexiou, Athanasios / Nizami, Bilal / Khan, Faez Iqbal / Soursou, Georgia / Vairaktarakis, Charalampos / Chatzichronis, Stylianos / Tsiamis, Vasilis / Manztavinos, Vasileios / Yarla, Nagendra Sastry / Md Ashraf, Ghulam. ·Novel Global Community Educational Foundation, Herbersham, Australia. · School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban 4000, South Africa. · Department of Chemistry, Rhodes University, Grahamstown 6139, South Africa. · Department of Computer Science and Biomedical Informatics, University of Thessaly, 35100 Lamia, Greece. · University of Southern Denmark, Department of Mathematics and Computer Science, Odense, Denmark. · Department of Biochemistry and Bioinformatics, School of Life Sciences, Institute of Science, GITAM University, Andhra Pradesh, India. · King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia. ·Curr Protein Pept Sci · Pubmed #28799502.

ABSTRACT: Disruptions in the regulation of mitochondrial dynamics and the occurrence of proteins misfolding lead to neuronal death, resulting in Age-related Dementia and Neurodegenerative diseases as well as Frailty. Functional, neurophysiologic and biochemical alterations within the mitochondrial populations can reveal deficits in brain energy metabolism resulting in Mild Cognitive Impairment, abnormal neural development, autonomic dysfunction and other mitochondrial disorders. Additionally, in cases of Alzheimer's disease or Parkinson's disease, a significant number of proteins seem to form unordered and problematic structures, leading through unknown mechanisms to pathological conditions. While the proteins structure prediction problem is still an open challenge regarding its complexity, several features associated with the correlations of misfolding proteins and Neurodegeneration are discussed in the present study and a computational analysis for the proteins Amyloid Beta, Tau, α-Synuclein, Parkin, Pink1, MFN1, MFN1, OPA1, and DNM1L is also presented.

9 Review Therapeutic, Molecular and Computational Aspects of Novel Monoamine Oxidase (MAO) Inhibitors. 2017

Ramesh, Muthusamy / Dokurugu, Yussif M / Thompson, Michael D / Soliman, Mahmoud E. ·Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban- 4001. South Africa. · Molecular Modeling and Drug Design Research Group, College of Pharmacy and Pharmaceutical Science Research Center, Florida Agricultural and Mechanical University (FAMU), Tallahassee, Florida 32307. United States. ·Comb Chem High Throughput Screen · Pubmed #28294055.

ABSTRACT: Background Due to the limited number of MAO inhibitors in the clinics, several research efforts are aimed at the discovery of novel MAO inhibitors. At present, a high specificity and a reversible mode of inhibition of MAO-A/B are cited as desirable traits in drug discovery process. This will help to reduce the probability of causing target disruption and may increase the duration of action of drug. AIM: Most of the existing MAO inhibitors lead to side effects due to the lack of affinity and selectivity. Therefore, there is an urgent need to design novel, potent, reversible and selective inhibitors for MAO-A/B. Selective inhibition of MAO-A results in the elevated level of serotonin and noradrenaline. Hence, MAO-A inhibitors can be used for improving the symptoms of depression. The selective MAO-B inhibitors are used with L-DOPA and/or dopamine agonists in the symptomatic treatment of Parkinson's disease. The present study was aimed to describe the recently developed hits of MAO inhibitors. METHOD: At present, CADD techniques are gaining an attention in rationale drug discovery of MAO inhibitors, and several research groups employed CADD approaches on various chemical scaffolds to identify novel MAO inhibitors. These computational techniques assisted in the development of lead molecules with improved pharmacodynamics / pharmacokinetic properties toward MAOs. Further, CADD techniques provided a better understanding of structural aspects of molecular targets and lead molecules. CONCLUSIONS: The present review describes the importance of structural features of potential chemical scaffolds as well as the role of computational approaches like ligand docking, molecular dynamics, QSAR and pharmacophore modeling in the development of novel MAO inhibitors.

10 Review Structural Exploration of Synthetic Chromones as Selective MAO-B Inhibitors: A Mini Review. 2017

Mathew, Bijo / Mathew, Githa Elizabeth / Petzer, Jacobus P / Petzer, Anel. ·Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad 678557, Kerala, India. · Department of Pharmacology, Grace College of Pharmacy, Palakkad 678004, Kerala, India. · Department of Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520. South Africa. ·Comb Chem High Throughput Screen · Pubmed #28245770.

ABSTRACT: AIM AND OBJECTIVE: Specific inhibitors of monoamine oxidase (MAO)-B are considered useful therapeutic agents in targeting neurological disorders like Alzheimer's and Parkinson's diseases. Due to the academic challenge of designing new hMAO-B inhibitors and the possibility of discovering compounds with improved properties compared to existing MAO-B inhibitors, a number of research groups are searching for new classes of chemical compounds that may act as selective hMAO-B inhibitors. MATERIALS AND METHODS: Among these, chromone (4H-1-benzopyran-4-one) derivatives have recently emerged as a chemotype with specific and high potency MAO-B inhibition. Chromones are structurally related to a series of coumarins and chalcones, which are well-known inhibitors of MAO-B. RESULTS: The experimental evidence has demonstrated that most of the chromone skeleton derived compounds have shown potent, reversible and selective type of hMAO-B inhibitors. CONCLUSION: The current review focuses on the MAO-B inhibitory properties of various synthetically derived chromones with specific emphasis on the structure-activity relationships and molecular recognition of MAO-B inhibition by this class. This review covers the recent updates present in the literature and will certainly provide a greater insight for the design and development of new class of potent chromone based selective MAO-B inhibitors.

11 Review Biology of GDNF and its receptors - Relevance for disorders of the central nervous system. 2017

Ibáñez, Carlos F / Andressoo, Jaan-Olle. ·Department of Physiology, National University of Singapore, Singapore 117597, Singapore; Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Neuroscience, Karolinska Institute, Stockholm S-17177, Sweden; Stellenbosch Institute for Advanced Study, Wallenberg Research Centre at Stellenbosch University, Stellenbosch 7600, South Africa. Electronic address: phscfi@nus.edu.sg. · Institute of Biotechnology, University of Helsinki, Helsinki 00014, , Finland. ·Neurobiol Dis · Pubmed #26829643.

ABSTRACT: A targeted effort to identify novel neurotrophic factors for midbrain dopaminergic neurons resulted in the isolation of GDNF (glial cell line-derived neurotrophic factor) from the supernatant of a rat glial cell line in 1993. Over two decades and 1200 papers later, the GDNF ligand family and their different receptor systems are now recognized as one of the major neurotrophic networks in the nervous system, important for the development, maintenance and function of a variety of neurons and glial cells. The many ways in which the four members of the GDNF ligand family can signal and function allow these factors to take part in the control of multiple types of processes, from neuronal survival to axon guidance and synapse formation in the developing nervous system, to synaptic function and regenerative responses in the adult. In this review, we will briefly summarize basic aspects of GDNF signaling mechanisms and receptor systems and then review our current knowledge of the physiology of GDNF activities in the central nervous system, with an eye to its relevance for neurodegenerative and neuropsychiatric diseases.

12 Review Parkinson disease and cognitive impairment: Five new things. 2016

Davis, Albert A / Racette, Brad. ·Department of Neurology (AAD, BR), Washington University School of Medicine, St. Louis, MO · and School of Public Health (BR), University of the Witwatersrand, Johannesburg, South Africa. ·Neurol Clin Pract · Pubmed #27847686.

ABSTRACT: PURPOSE OF REVIEW: While the distinctive motor symptoms of Parkinson disease (PD) have been described for centuries, cognitive impairment has only recently been recognized as a central feature. Studies have yielded clues to the etiology and natural history of cognitive impairment in PD, but much remains unclear and effective therapies are needed. RECENT FINDINGS: Longitudinal cohort studies demonstrate that almost all patients with PD will develop dementia if they live long enough. New CSF biomarker and genetic studies suggest that it may soon be possible to forecast and track the progression of dementia in PD. Sleep and sleep disturbance appear to be intrinsically linked with PD, although the implications for individual outcomes and opportunities for intervention are unclear. Multidisciplinary treatment approaches incorporating cognitive training may help to improve outcomes. SUMMARY: We review several recent advances in understanding the pathophysiology, genetics, and management of cognitive impairment in PD.

13 Review Synaptopathies: synaptic dysfunction in neurological disorders - A review from students to students. 2016

Lepeta, Katarzyna / Lourenco, Mychael V / Schweitzer, Barbara C / Martino Adami, Pamela V / Banerjee, Priyanjalee / Catuara-Solarz, Silvina / de La Fuente Revenga, Mario / Guillem, Alain Marc / Haidar, Mouna / Ijomone, Omamuyovwi M / Nadorp, Bettina / Qi, Lin / Perera, Nirma D / Refsgaard, Louise K / Reid, Kimberley M / Sabbar, Mariam / Sahoo, Arghyadip / Schaefer, Natascha / Sheean, Rebecca K / Suska, Anna / Verma, Rajkumar / Vicidomini, Cinzia / Wright, Dean / Zhang, Xing-Ding / Seidenbecher, Constanze. ·Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. · Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. · Department for Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Magdeburg, Germany. · Laboratory of Amyloidosis and Neurodegeneration, Fundación Instituto Leloir-IIBBA-CONICET, Buenos Aires, Argentina. · Department of Biochemistry, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal, India. · Systems Biology Program, Cellular and Systems Neurobiology, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain. · Universitat Pompeu Fabra, Barcelona, Spain. · Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, United States of America. · Laboratorio de Neurotoxicología, Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México D.F. 07000, Mexico. · Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia. · Department of Human Anatomy, Cross River University of Technology, Okuku Campus, Cross River, Nigeria. · The Department of Biological Chemistry, The Edmond and Lily Safra Center for Brain Sciences, The Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Israel. · Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, United States of America. · Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. · Department of Pharmacology, UCL School of Pharmacy, 29-39 Brunswick Square, London, WC1N 1AX, UK. · Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa. · Department of Biochemistry, Midnapore Medical College, West Bengal University of Health Sciences, West Bengal, India. · Institute for Clinical Neurobiology, Julius-Maximilians-University of Wuerzburg, Wuerzburg, Germany. · Department of Neurosciences Uconn Health Center, Farmington, CT, United States of America. · CNR, Institute of Neuroscience, Milan, Italy. · Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. · Department for Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology Magdeburg, Magdeburg, Germany. seidenc@lin-magdeburg.de. · Center for Behavioral Brain Sciences (CBBS) Magdeburg, Magdeburg, Germany. seidenc@lin-magdeburg.de. ·J Neurochem · Pubmed #27333343.

ABSTRACT: Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

14 Review Improving drug delivery technology for treating neurodegenerative diseases. 2016

Choonara, Yahya E / Kumar, Pradeep / Modi, Girish / Pillay, Viness. ·a Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Science, Faculty of Health Sciences , University of the Witwatersrand, Johannesburg , South Africa. · b Division of Neurosciences, Department of Neurology, Faculty of Health Sciences , University of the Witwatersrand, Johannesburg , South Africa. ·Expert Opin Drug Deliv · Pubmed #26967508.

ABSTRACT: INTRODUCTION: Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. AREAS COVERED: This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. EXPERT OPINION: Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase.

15 Review Advances in GBA-associated Parkinson's disease--Pathology, presentation and therapies. 2016

Barkhuizen, Melinda / Anderson, David G / Grobler, Anne F. ·DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa; Department of Paediatrics, School for Mental Health and Neuroscience, Maastricht University, Maastricht, 6229, The Netherlands. Electronic address: melinda.barkhuizen@gmail.com. · Department of Neurology, Witwatersrand University Donald Gordon Medical Centre, Parktown, Johannesburg, 2193, South Africa. · DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, 2520, South Africa. ·Neurochem Int · Pubmed #26743617.

ABSTRACT: GBA mutations are to date the most common genetic risk factor for Parkinson's disease. The GBA gene encodes the lysomal hydrolase glucocerebrosidase. Whilst bi-allelic GBA mutations cause Gaucher disease, both mono- and bi-allelic mutations confer risk for Parkinson's disease. Clinically, Parkinson's disease patients with GBA mutations resemble idiopathic Parkinson's disease patients. However, these patients have a modest reduction in age-of-onset of disease and a greater incidence of cognitive decline. In some cases, GBA mutations are also responsible for familial Parkinson's disease. The accumulation of α-synuclein into Lewy bodies is the central neuropathological hallmark of Parkinson's disease. Pathologic GBA mutations reduce enzymatic function. A reduction in glucocerebrosidase function increases α-synuclein levels and propagation, which in turn inhibits glucocerebrosidase in a feed-forward cascade. This cascade is central to the neuropathology of GBA-associated Parkinson's disease. The lysosomal integral membrane protein type-2 is necessary for normal glucocerebrosidase function. Glucocerebrosidase dysfunction also increases in the accumulation of β-amyloid and amyloid-precursor protein, oxidative stress, neuronal susceptibility to metal ions, microglial and immune activation. These factors contribute to neuronal death. The Mendelian Parkinson's disease genes, Parkin and ATP13A2, intersect with glucocerebrosidase. These factors sketch a complex circuit of GBA-associated neuropathology. To clinically interfere with this circuit, central glucocerebrosidase function must be improved. Strategies based on reducing breakdown of mutant glucocerebrosidase and increasing the fraction that reaches the lysosome has shown promise. Breakdown can be reduced by interfering with the ability of heat-shock proteins to recognize mutant glucocerebrosidase. This underlies the therapeutic efficacy of certain pharmacological chaperones and histone deacetylase inhibitors. These therapies are promising for Parkinson's disease, regardless of mutation status. Recently, there has been a boom in studies investigating the role of glucocerebrosidase in the pathology of Parkinson's disease. This merits a comprehensive review of the current cell biological processes and pathological pictures involving Parkinson's disease associated with GBA mutations.

16 Review Time to change the blind men and the elephant approach to Parkinson disease? 2015

Racette, Brad A / Willis, Allison W. ·From the Department of Neurology (B.A.R.), Washington University School of Medicine, St. Louis, MO · the School of Public Health (B.A.R.), Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa · and the Department of Neurology (A.W.W.) and the Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology and Biostatistics (A.W.W.), University of Pennsylvania School of Medicine, Philadelphia. ·Neurology · Pubmed #26070339.

ABSTRACT: Parkinson disease (PD) is a progressive neurodegenerative disease that is associated with substantial morbidity and early mortality. Disease-related costs exceed $10 billion, not including medications, out-of-pocket expenses, or societal costs. Symptomatic treatment with levodopa, which has been available for over 30 years, and advanced therapies such as deep brain stimulation improve outcomes. Yet most new medications for PD provide a therapeutic benefit that is relatively modest compared to the benefits from levodopa. Despite dozens of neuroprotective clinical trials, there are no medications proven to slow the progression of the disease. Given these limitations, we provide evidence of the potential public health impact of a research agenda that emphasizes identification of risk factors to reduce disease burden through exposure mitigation. In addition, we emphasize health care policy that focuses on increasing health care expenditures for neurologic evaluation and management services to increase access to specialists to improve disease outcomes and reduce costs through better disease management.

17 Review The dormant blood microbiome in chronic, inflammatory diseases. 2015

Potgieter, Marnie / Bester, Janette / Kell, Douglas B / Pretorius, Etheresia. ·Department of Physiology, Faculty of Health Sciences, University of Pretoria, Arcadia 0007, South Africa. · School of Chemistry and The Manchester Institute of Biotechnology, The University of Manchester, 131, Princess St, Manchester M1 7DN, Lancs, UK dbk@manchester.ac.uk. ·FEMS Microbiol Rev · Pubmed #25940667.

ABSTRACT: Blood in healthy organisms is seen as a 'sterile' environment: it lacks proliferating microbes. Dormant or not-immediately-culturable forms are not absent, however, as intracellular dormancy is well established. We highlight here that a great many pathogens can survive in blood and inside erythrocytes. 'Non-culturability', reflected by discrepancies between plate counts and total counts, is commonplace in environmental microbiology. It is overcome by improved culturing methods, and we asked how common this would be in blood. A number of recent, sequence-based and ultramicroscopic studies have uncovered an authentic blood microbiome in a number of non-communicable diseases. The chief origin of these microbes is the gut microbiome (especially when it shifts composition to a pathogenic state, known as 'dysbiosis'). Another source is microbes translocated from the oral cavity. 'Dysbiosis' is also used to describe translocation of cells into blood or other tissues. To avoid ambiguity, we here use the term 'atopobiosis' for microbes that appear in places other than their normal location. Atopobiosis may contribute to the dynamics of a variety of inflammatory diseases. Overall, it seems that many more chronic, non-communicable, inflammatory diseases may have a microbial component than are presently considered, and may be treatable using bactericidal antibiotics or vaccines.

18 Review Evidence for a common biological pathway linking three Parkinson's disease-causing genes: parkin, PINK1 and DJ-1. 2015

van der Merwe, Celia / Jalali Sefid Dashti, Zahra / Christoffels, Alan / Loos, Ben / Bardien, Soraya. ·Division of Molecular Biology & Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063, Cape Town, 7505, South Africa. ·Eur J Neurosci · Pubmed #25761903.

ABSTRACT: Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early-onset cases of PD are predominantly caused by mutations in the parkin, PINK1 and DJ-1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ-1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. DJ-1 is able to rescue the phenotype of PINK1-knockout Drosophila models, but not of parkin-knockouts, suggesting that DJ-1 may act in a parallel pathway to that of the PINK1/parkin pathway. To further elucidate a commonality between these three proteins, bioinformatics analysis established that Miro (RHOT1) interacts with parkin and PINK1, and HSPA4 interacts with all three proteins. Furthermore, 30 transcription factors were found to be common amongst all three proteins, with many of them being involved in transcriptional regulation. Interestingly, expression of these proteins and their associated transcription factors are found to be significantly down-regulated in PD patients compared to healthy controls. In summary, this review provides insight into common pathways linking three PD-causing genes and highlights some key questions, the answers to which may provide critical insight into the disease process.

19 Review Caffeine as a lead compound for the design of therapeutic agents for the treatment of Parkinson's disease. 2015

Petzer, Jacobus P / Petzer, Anel. ·Department of Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, 2520, South Africa. jacques.petzer@nwu.ac.za. ·Curr Med Chem · Pubmed #25544641.

ABSTRACT: The current pharmacological therapies for the treatment of Parkinson's disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson's disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson's disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson's disease.

20 Review Manganism in the 21st century: the Hanninen lecture. 2014

Racette, Brad A. ·Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8111, St. Louis, MO 63110, USA; University of the Witwatersrand, School of Public Health, Faculty of Health Sciences, Johannesburg, South Africa. Electronic address: racetteb@neuro.wustl.edu. ·Neurotoxicology · Pubmed #24148923.

ABSTRACT: Since the original description of the health effects of inhaled occupational manganese (Mn) by Couper in 1837, an extensive literature details the clinical syndrome and pathophysiology of what was thought to be a rare condition. In the last decade, conventional wisdom regarding the clinicopathological effects of Mn has been challenged. Past exposures to Mn were an order of magnitude higher than modern exposures in developed countries; therefore, the clinical syndrome seen in the time of Couper is no longer typical of modern Mn exposed workers. Parkinsonism (rigidity, bradykinesia, rest tremor, and postural instability) is present in 15% of Mn-exposed workers in welding industries, and these parkinsonian signs are associated with reduced health status and quality of life. These parkinsonian signs also overlap considerably with the clinical findings seen in early stages of Parkinson's disease (PD); although, molecular imaging suggests that Mn-exposed workers have dopaminergic dysfunction in a pattern unique from PD. Furthermore, geographic information system studies demonstrate that regions of the US with high industrial Mn emissions have an increased incidence of PD and increased PD associated mortality. This review will contrast historical, descriptive human studies in Mn-exposed subjects with more recent data and will suggest a research agenda for the 21st century.

21 Review The prevalence and genetics of Parkinson's disease in sub-Saharan Africans. 2013

Blanckenberg, Janine / Bardien, Soraya / Glanzmann, Brigitte / Okubadejo, Njideka U / Carr, Jonathan A. ·Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa. ·J Neurol Sci · Pubmed #24079843.

ABSTRACT: Parkinson's disease (PD) is under-studied in Black Sub-Saharan African (SSA) populations. To date, there have been only six prevalence and no incidence studies. The crude prevalence of PD in SSA varies from 7 to 20 per 100,000, which is appreciably lower than in Caucasian populations. There are a limited number of published studies (nine) on the genetic factors associated with PD in SSA populations. Mutations have been reported in the parkin gene, and are restricted to only three patients (two Black South Africans and one Zambian). No mutations have been identified in the LRRK2, SNCA, PINK, or DJ-1 genes. Given the unique ancestry of SSA populations, their inclusion in genetic studies may provide a substantial contribution to the identification of novel genetic factors and genetic-environmental interactions underlying this disorder. More initiatives are needed to drive further research on PD in these populations and to facilitate collaborative projects across Africa.

22 Review Attention and visual dysfunction in Parkinson's disease. 2012

Botha, Hugo / Carr, Jonathan. ·Division of Neurology, Department of Medicine, Faculty of Health Sciences, University of Stellenbosch, PO Box 19063, Tygerberg 7505, Cape Town, South Africa. ·Parkinsonism Relat Disord · Pubmed #22503538.

ABSTRACT: Visual processing extends from the retinal level to the ventral temporal lobe, and is modified by top-down and bottom-up processing. Complex visual hallucinations (VH) are commonly a feature of disorders which affect temporal lobe structures, frequently in association with impairment of ascending monoaminergic pathways. When Parkinson's disease (PD) is associated with VH, pathological changes characteristically affect the temporal lobes, a finding which is recapitulated by imaging findings. However, a major association of VH is with cognitive decline, and this is typically linked to deficits in attention and working memory, both of which are modulated by dopamine. Similarly, dopamine plays a crucial role in the function of prefrontal cortex, in addition to controlling access to consciousness via gating mechanisms that are dependent on the basal ganglia.

23 Review Genetic characteristics of leucine-rich repeat kinase 2 (LRRK2) associated Parkinson's disease. 2011

Bardien, Soraya / Lesage, Suzanne / Brice, Alexis / Carr, Jonathan. ·Division of Molecular Biology and Human Genetics, Stellenbosch University, Cape Town, South Africa. ·Parkinsonism Relat Disord · Pubmed #21641266.

ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive and selective degeneration of nigrostriatal dopaminergic neurons. The discovery of at least six PD-causing genes in predominantly early-onset forms of the disorder has cemented a genetic component to the etiology. Notably, the discovery of mutations in the LRRK2 gene in patients presenting with typical 'sporadic' PD with ages at onset in their sixties and seventies has shifted paradigms in the field of PD research. The G2019S mutation in LRRK2 has been found in diverse populations worldwide and usually resides on a common haplotype revealing that many of these individuals share a common ancestor, probably of Middle Eastern origin. The only validated coding susceptibility alleles for PD, G2385R and R1628P, are both in this gene but to date have been found exclusively in Asian populations. Concomitant with genetic testing for PD is the need for appropriate and informed genetic counseling. Families of patients with LRRK2 mutations and susceptibility alleles need to be informed about the current lack of disease preventative strategies and the implications surrounding incomplete penetrance. In summary, single-handedly LRRK2 has had a major impact on the field of PD research and the findings have been of interest to both clinicians and scientists. We anticipate that other genes of such major impact exist for PD and look forward to their discovery.

24 Review Advances in the treatment of neurodegenerative disorders employing nanotechnology. 2010

Modi, Girish / Pillay, Viness / Choonara, Yahya E. ·Department of Neurology, Division of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa. gmodicns@mweb.co.za ·Ann N Y Acad Sci · Pubmed #20146696.

ABSTRACT: Due to limitations posed by the restrictive blood-brain barrier, conventional drug delivery systems do not provide adequate cyto-architecture restoration and connection patterns that are essential for functional recovery in neurodegenerative disorders (NDs). Nanotechnology employs engineered materials or devices that interact with biological systems at a molecular level and could revolutionize the treatment of NDs by stimulating, responding to, and interacting with target sites to induce physiological responses while minimizing side effects. This review provides a concise discussion of the current applications of nano-enabled drug-delivery systems for the treatment of NDs, in particular Alzheimer's and Parkinson's diseases, and explores the future applications of nanotechnology in clinical neuroscience to develop innovative therapeutic modalities for the treatment of NDs.

25 Review Levodopa delivery systems: advancements in delivery of the gold standard. 2010

Ngwuluka, Ndidi / Pillay, Viness / Du Toit, Lisa C / Ndesendo, Valence / Choonara, Yahya / Modi, Girish / Naidoo, Dinesh. ·University of the Witwatersrand, Department of Pharmacy and Pharmacology, 7 York Road, Parktown, 2193, Johannesburg, South Africa. ·Expert Opin Drug Deliv · Pubmed #20095943.

ABSTRACT: IMPORTANCE OF THE FIELD: Despite the fact that Parkinson's disease (PD) was discovered almost 200 years ago, its treatment and management remain immense challenges because progressive loss of dopaminergic nigral neurons, motor complications experienced by the patients as the disease progresses and drawbacks of pharmacotherapeutic management still persist. Various therapeutic agents have been used in the management of PD, including levodopa (l-DOPA), selegiline, amantadine, bromocriptine, entacapone, pramipexole dihydrochloride and more recently istradefylline and rasagiline. Of all agents, l-DOPA although the oldest, remains the most effective. l-DOPA is easier to administer, better tolerated, less expensive and is required by almost all PD patients. However, l-DOPA's efficacy in advanced PD is significantly reduced due to metabolism, subsequent low bioavailability and irregular fluctuations in its plasma levels. Significant strides have been made to improve the delivery of l-DOPA in order to enhance its bioavailability and reduce plasma fluctuations as well as motor complications experienced by patients purportedly resulting from pulsatile stimulation of the striatal dopamine receptors. AREAS COVERED IN THIS REVIEW: Drug delivery systems that have been instituted for the delivery of l-DOPA include immediate release formulations, liquid formulations, dispersible tablets, controlled release formulations, dual-release formulations, microspheres, infusion and transdermal delivery, among others. In this review, the l-DOPA-loaded drug delivery systems developed over the past three decades are elaborated. WHAT THE READER WILL GAIN: The ultimate aim was to assess critically the attempts made thus far directed at improving l-DOPA absorption, bioavailability and maintenance of constant plasma concentrations, including the drug delivery technologies implicated. TAKE HOME MESSAGE: This review highlights the fact that neuropharmaceutics is at a precipice, which is expected to spur investigators to take that leap to enable the generation of innovative delivery systems for the effective management of PD.