Day 1 :
Keynote Forum
Kjell Fuxe
Karolinska Institutet, Sweden
Keynote: Nigro-striatal DA neurons in the world of volume transmission and heteroreceptor complexes: Relevance for Parkinson’s disease
Time : 10:00-10:40
Biography:
Kjell Fuxe has been a Professor of Histology at Karolinska Institutet since 1979. He was the Member of Nobel Assembly during 1986-2005. He achieved his Honorary Doctorates at the Universities of Barcelona, Ferrara, Malaga, at Universite Claude Bernard, Lyon, at Marquis Guiseppe Scicluna International University Foundation and at the Albert Einstein International Academy Foundation. He has received a significant number of awards and published over 1500 papers in neuroscience. 1209 of them are found in Pubmed. His major achievements involve pioneering work on central monoamine neurons, the existence of volume transmission, receptor-receptor interactions in heteroreceptor complexes and in neuro-endocrinology and neuro-psychopharmacology.
Abstract:
The nigro-striatal DA neurons mainly operate via volume transmission (VT). The major difference of synaptic transmission vs. volume transmission is found in the channels which are private in synaptic transmission (axons and terminals) but diffuse in VT represented by the channel plexus of the extracellular space including paravascular channels and the CSF. There exist different forms of VT: Extrasynaptic, long distance, CSF and extracellular vesicle mediated VT. Interleukin-1b (IL-1b) may produce inflammation and sickness behavior via long distance and CSF VT. The balance and integration of VT and synaptic transmission mainly takes place through receptor-receptor interactions in heteroreceptor complexes in the plasma membrane and or their signaling cascades including also the signaling from the corresponding receptor homomers. It appears crucial for CNS communication and of high relevance for psychiatric diseases and neurological diseases like Parkinson’s disease. The allosteric receptor-receptor mechanism causes a marked rise of the repertoire of GPCR recognition, pharmacology, trafficking and signaling of the participating receptor protomers. We have introduced the moonlighting concept into the GPCR heteromer field, since GPCR protomers can change their function through the allosteric receptor-receptor interactions. This is achieved through changes in recognition, G protein selectivity and signaling via other proteins involved, for example, a switch from G proteins to b-arrestin through conformational changes in single or several strands of amino acids. The fields of receptor-receptor interactions in GPCR containing heteroreceptor complexes and protein–protein interactions, in general, have opened up new targets for drug development and several strategies can be exploited to develop new drugs based on targeting the heteroreceptor complexes. The striatal A2A-D2 heteroreceptor complexes were proposed to be an important target for antiparkinsonian drugs based on the existence of antagonistic A2A-D2 receptor-receptor interactions within them. This strongly contributed to the introduction of A2A receptor antagonists in the treatment of Parkinson’s disease.
Keynote Forum
Michael Ugrumov
Institute of Developmental Biology RAS, Russia
Keynote: Advanced methodology for the development of preclinical diagnostics of Parkinson’s Disease
Time : 10:40-11:20
Biography:
Michael Ugrumov is a academician of Russian Academy of Sciences and completed his MD at Institute of Evolutionary Physiology & Biochemistry (Leningrad), PhD at Institute of Developmental Biology, Professorship at University Medical School (Moscow). He is the Head of Laboratory of Neural and Neuroendocrine Regulations at institute of Developmental Biology RAS, Vice-President of Russian Physiological Society. He is a member of European Academy of Science and Arts, Serbian Academy of Science and Arts, French National Academy of Pharmacy. He has published more than 200 papers in peer reviewed journals and served as an editorial board member of 8 International and Russian journals.
Abstract:
Motor symptoms first appear at Parkinson’s disease (PD) long after the onset of the degradation of the nigrostriatal dopaminergic (DA-ergic) system, at a loss of most specific neurons and depletion of neuroplasticity, which explains low efficiency of traditional treatment. Therefore, the development of the diagnostics at the preclinical stage is of the highest priority. Current methodology of this technology is based on a systemic character of PD and search in non-treated patients at the early clinical stage for biomarkers, such as the non-motor clinical symptoms and changes in the composition of body fluids (blood, CSF) and expression of specific genes and syntheses in blood cells. It is of particular importance if in addition to patients there is a search for peripheral biomarkers in experimental models of PD at preclinical stage. Fundamentally novel approach for the diagnostics of PD was recently developed in our laboratory using the original model of preclinical PD. It is based on the applying of the provocation test inducing a reversible enhancing a latent failure of the DA-ergic system and temporal appearance of motor disorders. The detection of peripheral biomarkers and positive provocation test in people under a prophylactic examination with no motor disorders would allow to include them in a risk group for final diagnosing of PD at the preclinical stage with positron emission tomography. Development of preclinical diagnostics of PD will give an opportunity of using neuroprotective pharmacotherapy for slowing down neurodegeneration and thereby prolongation of a period of comfort life of patients.
- Associate Disorders like Neurocognitive and Degenerative Disorder, Diagnostic Approaches for Parkinsons Disease
Location: Raume / Room - 4
Chair
Ekaterina Rogaeva
University of Toronto, Canada
Session Introduction
George Stoica
Texas A&M University, USA
Title: Movement Disorder and Neurodegeneration in a Rat Model with Myosin 5a Mutation
Time : 11:40-12:10
Biography:
George Stoica, DVM, MSc., PhD is a professor in the department of Veterinary Pathobiology at Texas A&M University, USA. He received his master degree in veterinary pathology from Ohio State University and PhD in experimental pathobiology from Michigan State University. He is with Texas A&M University since 1984 and advanced to full professor in 1996. His area of expertise is in experimental neuropathology and his area of research span from chemical carcinogenesis, viral carcinogenesis, comparative neurooncology and neurodegenerative disorders in animal models. He published over 100 scientific articles in peer review journals and wrote several chapters in various books.
Abstract:
Myosin5a (Myo5a) is an actin-dependent motor protein that is highly expressed in the brain, and involved in vesicular/organelles transport and its absence leads to movement disorders in humans and animal species (Griscelli and Elejalde syndromes in humans), rodents (dilute lethal phenotype in mice, and diluteopisthotonus of Wistar rats), and Arabian horses Lavender Foal Syndrome. A spontaneous autosomal recessive rat model for neurodegeneration caused by a mutation in the Myo5a gene was developed in our laboratory. The pleiotropic effects of this mutation affect the coat color, central nervous and neuroendocrine systems. Preliminary data from our model of Myo5a mutant Berlin-Druckrey (BD-IV) “shaker” rats demonstrated marked alterative changes involving the alpha-synuclein (α-syn) overexpression, decrease dopamine (DA) levels, alteration of DA metabolism, and overexpression of tau protein in specific anatomical areas of brain in shaker rats compared with non-affected siblings. The movement disorder and alterative biochemical changes increased in severity after 15 days postnatal. The mechanisms responsible for neurological phenotypes in the deficient Myo5a affected animals are less understood and deserve further investigation. Possible role of diverse myosins in synaptic transmission or plasticity has not been investigated. Similar neurological degenerative changes are common in human neurodegenerative diseases such as Alzheimer, Parkinson’s, and Lewis Body dementia, which make this animal model ideal for mechanistically investigating human diseases with potential development of novel therapy, which can lead to translational studies. The main challenge for the future will be to investigate the molecular mechanisms of Myo5a neurodegeneration and its interaction with other proteins underlying its functions.
Ekaterina Rogaeva
University of Toronto, Canada
Title: Mutation analysis of CHCHD10 in neurodegenerative diseases, including Parkinson’s disease
Time : 12:10-12:40
Biography:
Dr. Ekaterina Rogaeva obtained her PhD in Biochemistry at Moscow State University (Russia) in 1988. Researcher, Tanz Centre for Research in Neurodegenerative Diseases, she is an associate professor form university of Toronto. She played a central role in the discovery and characterization of the two presenilin genes responsible for the most aggressive early-onset form of Alzheimer’s disease.
Abstract:
A recent study by Bannwarth et al. implicated CHCHD10 as a novel gene for amyotrophic lateral sclerosis/frontotemporal lobar degeneration (ALS/FTLD). Affected family members were presented with a complex phenotype that included symptoms of ALS, FTLD, cerebellar ataxia, Parkinson's disease (PD) and a mitochondrial myopathy associated with multiple mitochondrial DNA deletions. So far, seven missense CHCHD10 mutations have been reported in patients with a broad phenotypic range. Notably, mitochondrial dysfunction has been implicated in several neurodegenerative diseases. Hence, we sequenced CHCHD10 in 204 ALS, 153 PD, 158 FTLD and 141 Alzheimer’s disease (AD) patients, as well as 497 normal controls. We identified two known pathogenic mutations in three ALS patients (p.R15L and p.P80L); as well as two novel substitutions in two FTLD patients (p.P23T and p.A35D). Finally, we detected a p.P34S substitution in PD patient, who has no symptoms of muscle weakness, dementia or ALS. The same p.P34S variant was also detected in two AD cases, but it did not segregate with AD in the available family. The p.P34S variant was previously reported in unrelated FTLD/ALS and ALS patients. However, the p.P34S substitution was found at comparable frequencies in our control samples and public databases, suggesting that this variant is not pathogenic, which is important in the utility of genetic screening in patient care. The frequency of the CHCHD10 mutations in our datasets is 2.6% for familial ALS, 1.2% for sporadic ALS, 1.6% for familial FTLD, and 1% for sporadic FTLD. All mutation carriers are characterized by atypically long duration and slow disease progression. In conclusion, our study supports the causal role of CHCHD10 mutations in both ALS and FTLD, but not in AD or PD. Intriguingly, the mutations in the CHCHD2 gene (structurally similar to CHCHD10) were very recently reported to cause PD in Japanese patients. The mutation analysis of CHCHD2 in Canadian PD dataset is ongoing and will be presented.
Soliman Khatib
MIGAL–Galilee Research Institute, Israel
Title: Analysis of volatile organic compounds in rats with dopaminergic lesion: possible application for early detection of Parkinson’s disease
Time : 12:40-13:10
Biography:
Soliman Khatib, now is a Research Associate in the laboratory of oxidative stress Migal-Galilee Research institute and a Senior lecturer, Department of Biotechnology Tel-Hai academic collage. Doctor's degree (Ph.D.) (direct Ph.D. program), Technion institute, Natural Science, Chemistry1996-2000. BSC, Ben-Gurion University, Natural Science, Chemistry 1993-1995. My research focus on understanding the relationship between oxidative stress and diseases related to oxidative stress, we identify volatile organic compounds (VOCs) as early biomarkers of Parkinson and other neurodegenerative diseases.
Abstract:
Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron depletion. Early detection of PD may help in selecting the appropriate treatment. Biomarkers of PD have been suggested, however none of these is currently in clinical use. The aim of this study was to identify volatile organic compounds (VOCs) as early biomarkers of PD. Our hypothesis was that during PD progression, specific VOCs are generated that are linked to the biochemical pathways characterizing PD. These VOCs can be detected by GC–MS combined with solid-phase microextraction (SPME) technique. Three groups of rats were studied: DA-lesioned rats injected with 6-hydroxydopamine (HDA; 250 μg/rat n=11); control rats injected with saline (n=9), and control rats injected with DSP-4 (n=8), a specific noradrenergic neuron toxin. Blood and striatal tissue homogenate were analyzed. In the blood, 1-octen-3-ol and 2-ethylhexanol were found at significantly higher concentrations in HDA versus sham rats. In the striatal homogenate 1-octen-3-ol and other four compounds were found at significantly lower concentrations in HDA versus sham rats. 1-Octen-3-ol is a cytotoxic compound. These results may lead to the development of an early diagnostic test for PD based on profiling of VOCs in body fluids.
Kazumasa saigoh
Kinki University, Japan
Title: The concentration of oxidized DJ-1 protein (oxDJ-1) in red blood cells is useful for the diagnosis method of Parkinson\\\'s disease
Time : 14:00-14:30
Biography:
Kazumasa Saigoh, M.D., Ph.D. born in Osaka, Japan. He had medical and graduate training at the Kinki University Faculty of Medicine Department of Neurology and received his PhD in 1999. He worked Post-doc at the National Center of Neurology and Psychiatry of Japan. He specialized in Neurogenetics and Circadian rhythm in 2000-2003 at the Howard Hughes medical institute in University of Utah. In 2004, he give a position as Lecturer of Kinki University Faculty of Medicine, teaching Neurogenetics and Neurology. In 2015, He served concurrently as Associate professor at the Kinki University Faculty of Science and Engineering, Department of Life Science.
Abstract:
Parkinson disease (PD) are the most common neurodegenerative disorders. Although PD diagnosis is difficulty among Progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and PD. Examination of biomarkers of Parkinson’s disease PD usually focuses on the factors in the cerebrospinal fluid, and there are very few reports on simple biomarkers identified by blood analysis. We determined the level of oxidized DJ-1 protein (oxDJ-1) in red blood cells by the ELISA method. The level of oxDJ-1 was 124.07 ± 13.7 ng oxDJ-1/mg protein in 43 un-treated PD patients group; 88.0 ± 29.8 ng oxDJ-1/mg protein in 9 PSP patients group and 98.8 ± 13.9 ng oxDJ-1/mg protein in 5 MSA patients group. The mean level in 17 control group was 56.0 ± 6.2 ng oxDJ-1/mg protein, showing significant intergroup differences. The clinical courses after intervention with L-dopa treated PD showed a tendency toward decreasing oxDJ-1 levels in the same patient. Our results showed that measurement of oxDJ-1 levels in red blood cells is useful and oxDJ-1 can be used as a biomarker for the early diagnosis of Parkinson’s disease.
- Workshop
Location: Raume / Room - 4
Session Introduction
Dasiel O Borroto-Escuela
Karolinska Institutet, Sweden
Title: On the role of A1-D1 heteroreceptor complexes in the direct pathway in models of Parkinson’s disease
Time : 14:30-16:00
Biography:
Dasiel O Borroto-Escuela has completed his PhD from Polytechnic University of Catalonia, Spain. Since 2009, he has been a Contracted Postdoctoral Researcher at the Department of Neuroscience, Karolinska Institutet. His primary focus is on understanding whether alterations in specific heteroreceptor complexes and if their receptor-receptor interactions are associated with and/or play a role in pathogenetic mechanisms contributing to brain disease development, inter alia Parkinson’s disease, schizophrenia, addiction and depression. He has received a significant number of awards, among which are the UPC Excellence Thesis Award, the FEBSYSF 2013, the ECNP 2014 Fellow Award. He has published over 70 papers in neuroscience in the last five years. His major achievements involve pioneering work on understanding the molecular integration of signals in the brain via receptor-receptor interaction in heteroreceptor complexes and its functional effects also, in the implementation of new innovative tools and screening technologies to identify GPCR oligomers.
Abstract:
Among a large number of behavioural studies on adenosine A1-Dopamine D1 receptor interactions, a few examples may be given. Thus, the A1 receptor agonist CPA counteracted the D1 receptor agonist (SKF 38393)-induced grooming behavior and counteracted dyskinetic behavior in rabbits. In line with these results, the A1 receptor antagonist CPT enhanced the motor activating effects of the D1 agonist SKF 38393 in reserpinized mice and in rat models of Parkinson’s disease (unilateral 6-OH-dopamine lesions of the nigrostriatal dopamine pathway). This behavioural result at the network level indicates the existence of antagonistic A1-D1 receptor interactions. The molecular basis of the antagonistic A1-D1 receptor interaction likely involves the existence of A1-D1 heteroreceptor complexes in the direct pathway. The A1-D1 heteroreceptor complexes may reflect a direct physical interaction without the involvement of an adapter protein, since specific BRET and FRET signals can be detected between fluorescent-tagged A1 and D1 receptors upon transient co-transfection in cell lines. Furthermore, in situ Proximity Ligation Assay clearly demonstrated that A1 and D1 receptors exist as heteroreceptor complexes in rat brain. Antagonistic A1-D1 interactions also exist at the level of the second messengers. These results suggest a role of A1 receptor agonists and antagonists in the treatment of Parkinson’s disease with dysfunction of D1 receptor signaling via their actions on the A1-D1 heteroreceptor complexes located in the direct pathway. A1 agonists may, for example, reduce levodopa induced dyskinesias. It will be of substantial interest to know how the A1-D1 receptor interaction may regulate trophic mechanisms such as neurotrophic factors and neuronal differentiation.
- Basic Science & Epidemiology and Pathophysiology & Neuro pharmacology
Location: Raume / Room - 4
Chair
Michael Ugrumov
Institute of Developmental Biology RAS, Russia
Session Introduction
Eman Khedr
Assiut University, Egypt
Title: Prevalence of Parkinson’s disease in Egypt: A review of community-based survey
Time : 16:30-17:00
Biography:
Eman M Khedr has done her Post-Doctorate Training course in Neurophysiology in Gentoft Hospital, Copenhagen (Denmark) 1998 supervised by Professor Fredrekson; and a training course for diagnosis and management of Parkinson Disease Patients in Oregon University Hospital (Portland) 2000, supervised by Professor John Nutt. She achieved a Postdoctoral Fellowship to study methods of measuring cortical excitability in different diseases for 3 months in Sobell Department of Motor Neuroscience and Movement Disorders, National Hospital for Neurology and Neurosurgery, Queen Square, London.
Abstract:
Introduction: There are few community-based studies of Parkinson’s disease (PD) from Arabic countries; 4 of them have been performed in Egypt. Such studies are more informative than hospital-based data in countries with a large rural population such as Egypt where people may not be able to come to hospital for treatment. Material & Methods: A systematic search of Medline and Global Health for original population-based studies on Parkinson’s disease was conducted. We found only 4 community-based studies that were done in different Egyptian governorates including, Assiut, Al Kharga, Al Quseir and Qena. Results: Overall the recorded Crude Prevalence Rate (CPR) of Parkinson’s disease in Egypt was varied in different governorates and ranged from 53 to 557/105 inhabitants (all ages) and the CPR of PD ranging from 213.15 to 2748/105 among the population aged >40 or >50 years. The crude incidence rate was ranging from 82-62/105 (all ages) with male to female ratio 4:1. The highest age-specific CPR was recorded among subjects >75 years old. The CPR showed a tendency to be higher in males than females and in industrial than non-industrial areas. There was a significantly higher CPR among illiterate than literate persons. About one quarter of patients had cognitive impairment (14.3-22.3%). All cases had positive symptoms in at least one or more NMS Domains. Conclusion: The overall prevalence of PD disease is high in Nile Valley governorates of Upper Egypt compared to other Arabic countries.
Ashton Rogers
The University of the West Indies, West Indies
Title: The effect of systemic inflammation induced by a high sucrose diet on inflammation in the rat substantia nigra
Time : 17:00-17:30
Biography:
Ashton Rogers, the first person in the English speaking Caribbean to be awarded a PhD in Neuroscience by The University of the West Indies, is very enthusiastic about better understanding the relationship between diet, metabolic syndrome and neuroinflammation in the substantia nigra. After graduating in 2014, he founded the first Neuroscience Centre of Trinidad and Tobago, a non-profit organization aimed at promoting brain health awareness and improving the welfare of patients affected with neurological diseases. He is presently establishing the first Neuroscience Foundation of Trinidad and Tobago, a charity organization to sponsor patients in need of foreign treatment.
Abstract:
Animal studies robustly demonstrate that systemic inflammation evoked by bacterial endotoxin can potentiate inflammation in the brain through the activation microglial cells. However, it is unclear if systemic inflammation associated with Metabolic Syndrome (MetS) can affect neuroinflammation in the Substantia Nigra (SN). MetS is primarily caused by obesity due to a high sucrose diet. The objective of this research is to determine if systemic inflammation induced by a high sucrose diet can affect an ongoing inflammatory process in the rat SN. Sprague Dawley rats were given a stereotaxic intranigral injection of either a normal dose (2.0 μg, n=40) or a low dose (0.2 μg, n=40) of Lipopolysaccharide (LPS) to trigger a high level or benign inflammatory process, respectively. The groups were then sub-divided and provided with either normal drinking water or drinking water with 30% sucrose (w/v) for 30 days. All rats were fed standard rat chow. Immunocytochemistry was used to assess morphological changes of microglial cells, astrocytes and dopamine neurons in the SN. Real-time RT-PCR was used to assess an array of pro and anti-inflammatory markers in the SN, adipose tissue and liver. The results show that the sucrose-fed rats exhibited a higher level of neuroinflammation in the SN. Interestingly, the group injected with the low dose of LPS and provided with sucrose displayed the highest level of inflammation. These findings support the hypothesis that a high sucrose diet and the resulting systemic inflammation can exacerbate a benign inflammatory process in the SN, thus increasing the risk of developing PD.