Eri Kawashita1, Daisuke Tsuji2, Kohji Itoh2*

1Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Kyoto, Kyoto, Japan
2Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima, Tokushima, Japan

 Sandhoff disease (SD) is an inherited lysosomal storage disease caused by a β-hexosaminidase deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside, which leads to neurological symptoms, such as mental retardation, spasms and quadriplegia. Macrophage inflammatory protein-1α (MIP-1α) is a crucial factor for microglia-mediated neuroinflammation in the onset or progression of SD. However, there was no therapeutic approach to control the abnormal production of MIP-1α in the brain of SD, and the mechanisms underlying the MIP-1α production by microglia, especially the transmitter-mediated production, remains unclear.

Extracellular nucleotides, including uridine diphosphate (UDP), are leaked by injured or damaged neurons. It has been shown that the nucleotide leakage activates microglia to trigger chemotaxis, phagocytosis, macropinocytosis and cytokine production, suggesting that extracellular nucleotides may be important neurotransmitters for microglia to regulate their functions physiologically and pathologically.

In the present study, we review the essential roles of extracellular nucleotides in the microglial functions and the UDP-enhanced MIP-1α production by microglia in SD model mice, providing a potential therapeutic approach for SD.

DOI: 10.29245/2572.942X/2016/7.1074 View / Download Pdf

Víctor Danelon1, Andrea B. Cragnolini1, Daniel Masco1*

1Laboratorio de Neurobiología, Instituto de Investigaciones Biológicas y Tecnológicas, IIByT-CONICET-FCEFyN, Universidad Nacional de Córdoba, Av. Vélez Sarsfield 1611, Córdoba, Argentina.

Several neurological conditions share a characteristic feature: an increase in intracellular calcium levels ([Ca2+]i). It has been demonstrated that calcium influx induces changes ranging from an increase in the expression levels of several genes to the activation of proteases such as calpains. Calpains are a family of Ca2+-dependent non-lysosomal cysteine proteases, whose substrates include several proteins that play critical roles in several cellular functions including synaptic plasticity and neuronal apoptosis.

TrkB is a type of tyrosine related kinase receptor that can promote neuronal survival and differentiation upon ligand binding. It has been recently shown that in several neurological diseases, the level of full-length TrkB protein decreases before the onset of neuronal death due to one of two different processes: a) a reverse regulation of TrkB isoforms mRNA, or b) calpain-mediated processing of TrkB full-length, which yields a truncated form of TrkB (Tc-TrkB). Because the most notorious feature of calpain proteolytic activity is that the products of calpain-mediated cleavage may have biological activity, here we review the hypotheses by which calpain-generated isoform Tc-TrkB may perform biological functions.

DOI: 10.29245/2572.942X/2016/7.1076 View / Download Pdf

Claudia Barzago1, Pia Bernasconi1, Raffaele A. Calogero2, Carlo Antozzi1, Francesca Zolezzi3, Renato Mantegazza1# and Lucia Mori4*

1Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Foundation Neurological Institute "Carlo Besta", 20133 Milan, Italy
2Molecular Biology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy
3GALDERMA R&D, 06902 Sophia Antipolis Cedex, France
4Experimental Immunology, Department of Biomedicine, University Hospital Basel and University of Basel, 4031, Basel, Switzerland

Early-onset acetylcholine receptor-positive myasthenia gravis is the most studied and better-characterized clinical subgroup of myasthenia gravis. Here we discuss the results of the first comprehensive and unbiased transcriptome sequencing analysis performed on circulating cells of a clinically homogeneous cohort of patients affected by this disease form.

DOI: 10.29245/2572.942X/2016/7.1081 View / Download Pdf

Anika M. Helferich1, Pamela J. McLean2, Jochen H. Weishaupt1 and Karin M. Danzer1*

1Department of Neurology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany
2Mayo Clinic, Jacksonville, Florida, USA

Alpha-synuclein and Cu, Zn superoxide dismutase (SOD1) are both aggregation-prone proteins that are associated with Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), respectively. Recently, we showed that alpha-synuclein interacts with SOD1 in various cell types and tissues. Using a cell culture model, we also found that alpha-synuclein nucleates the polymerization of SOD1. Here, we discuss the current literature regarding their interaction and their co-localization in aggregates of human post-mortem tissue. Furthermore we comment on the reported alpha-synuclein-induced SOD1 polymerization in terms of cross-seeding effects in neurodegeneration.

DOI: 10.29245/2572.942X/2016/7.1065 View / Download Pdf

Simon Wing Fai Mok, Vincent Kam Wai Wong, Betty Yuen Kwan Law*

State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China

Chronic diseases are the leading causes of physical impairments and mortality in the world. The functional role of autophagy in maintaining cellular homeostasis implies that the molecular machinery is a compelling pharmaceutical target for such disorders involving overall body imbalance. Therefore, autophagy modulators appeared to be the ideal source for hunting of novel and effective pharmaceutical interventions. Law et al., have performed a systematic review on more than 30 different Chinese herbal medicine (CHM)-derived bioactive compounds capable of regulating autophagy activity. The successful experimental and clinical applications of these compounds which have not been previously documented have been discussed. Notably, most of the reported novel applications are associated with chronic dysfunctions.

DOI: 10.29245/2572.942X/2016/7.1070 View / Download Pdf

Milena A. Gianfrancesco and Lisa F. Barcellos*

Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA

Several studies conducted around the world over the last decade have demonstrated that early childhood and adolescent obesity are significant risk factors for MS susceptibility. This association has been largely confirmed in females, while evidence supporting a strong role for obesity and risk of MS in males has been mixed. Further, interaction between increased body mass index and genetic as well as environmental factors in MS susceptibility has been proposed, and evidence of a causal relationship has recently been established. In this review, we discuss findings supporting the significant association between obesity and MS, as well as identify areas for future investigation.

DOI: 10.29245/2572.942X/2016/7.1064 View / Download Pdf

Lara A. Haeusser, Lothar Kanz, Marcus M. Schittenhelm, Kerstin M. Kampa-Schittenhelm*

University Hospital Tübingen, Dept. of Oncology, Hematology, Clinical Immunology, Rheumatology and Pulmology, Tübingen, Germany

The endocannabinoid system is extensively studied in neuroscience and clinical use of cannabinoid derivatives as substances with remarkable spasmolytic effects in multiple sclerosis and antiemetic potential in cancer therapy as well as pain-relieving properties is broadly acknowledged.

However, it becomes increasingly apparent, that in addition cannabinoids exert manifold functions in various organ systems, such as the immune system, the reproductive or cardiovascular system among others. Moreover, interactions with signaling pathways involved in programmed cell death, angiogenesis, metastasis or anti-tumor immunity make it highly suggestive that cannabinoids may have therapeutic potential in the treatment of cancer. Indeed, detailed reports have repeatedly shown anticancer efficacy in solid and hematologic tumor models, best characterized in human gliomas.

Anecdotal evidence of blast control in a young patient with acute myeloid leukemia has led us to systematically investigate the potential use of cannabinoids in the treatment of acute leukemia.

Owing to the critical cellular role of lysosomes in the myelination, mounting studies focus on the mechanisms underlying exocytosis of lysosome in nervous system has emerged. In this paper, we briefly introduce the recent advances in this respect.

These data are summarized herein in the context of key data regarding anticancer efficacy of cannabinoids.

DOI: 10.29245/2572.942X/2016/6.1053 View / Download Pdf

John F. Crary

Department of Pathology, Fishberg Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer’s Disease,Icahn School of Medicine at Mount Sinai, USA

Extensive data supports the amyloid cascade hypothesis, which states that Alzheimer’s disease (AD) stems from neurotoxic forms of the amyloid-beta(Aβ)peptide. But the poor correlation between Aβ plaques and neurodegeneration/cognitive impairment, the spaciotemporal disparity between Aβ and tau pathology, and the disappointing results following several large clinical trials using Aβ-targeting agents are inconsistent with this explanation. The most perplexing inconsistency is the existence of AD-type dementia patients that develop abundant neurofibrillary tangles that are indistinguishable from those in early to moderate-stage AD in the absence of compelling evidence of amyloid toxicity. This neuropathological phenotype, which is distinct from other diseases with tangles, represents a conceptual disconnect, because it does not fall within any previously established category of tauopathy and ostensibly invalidates the amyloid cascade hypothesis. Instead, recent efforts have led to consensus criteria for a new alternative diagnostic category, which presupposes that these tangle-only dementia patients represent extreme examples of a distinct primary age-related tauopathy (PART) that is universally observed, albeit to varying degrees, in the aging brain. The cause of PART is unknown, but sufficient evidence exists to hypothesize that it stems from an Aβ-independent mechanism, such as mechanical injury. Should the PART hypothesis withstand further experimental testing, it would represent a shift in the way a subset of subjects with AD neuropathological change are classified and has the potential to focus and reaffirm the amyloid cascade hypothesis.

DOI: 10.29245/2572.942X/2016/6.1059 View / Download Pdf

Rohit Aiyer1*, Lynne Voutsinas2, Yasir El-Sherif3

1Department of Psychiatry, Hofstra Northwell Health - Staten Island University Hospital, USA
2Department of Radiology, Hofstra Northwell Health – Staten Island University Hospital, USA
3Department of Neurology, Hofstra Northwell Health – Staten Island University Hospital, USA

DOI: 10.29245/2572.942X/2016/6.1050 View / Download Pdf

Alejandro K. Samhan-Arias1*, Carmen López-Sánchez2*, Dorinda Marques-da-Silva1, Ricardo Lagoa1,2,3Virginio Garcia-Lopez2,4, Virginio García-Martínez2Carlos Gutierrez-Merino1,#

1Dept. Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, 06006-Badajoz, Spain
2Dept. Human Anatomy and Embryology, Faculty of Medicine, University of Extremadura, 06006-Badajoz, Spain
3ESTG- Polytechnic Institute of Leiria, Leiria, Portugal
4FARMADIEX 06008 Badajoz, Spain

Cytochrome b5 reductase (Cb5R) and cytochrome b5 (Cb5) are coupled redox systems with a high potential as biomarkers of health and disease in the brain because they regulate metabolic pathways that are essential to maintain normal neuronal function, like lipid biosynthesis, steroid and xenobiotics metabolism, neuronal bioenergetics and production of reactive oxygen species. Mutations of the Cb5R reported in humans produce recessive congenital methemoglobinemia of type II, a disease with severe clinical neurological dysfunctions. The isoform 3 of Cb5R (Cb5R3) and Cb5 are highly expressed in pyramidal neurons of the primary and secondary motor areas of frontoparietal cerebral cortex, hippocampus, vestibular, reticular and motor nuclei of the cerebellum and brain stem, and also in Purkinje and granule neurons of the cerebellum cortex. These brain areas are highly prone to undergo oxidative stress-induced neurodegeneration and their functional impairment can account for neurological deficits reported in type II congenital methemoglobinemia.

DOI: 10.29245/2572.942X/2016/6.1066 View / Download Pdf

Erna A. van Niekerk*

Department of Neurosciences-0626, University of California, San Diego, La Jolla, CA 92093, USA

 Spinal cord injury (SCI) research continues to make substantial progress in identifying both neuron-intrinsic and neuron-extrinsic mechanisms that limit central nervous system (CNS) plasticity and regeneration. The identification of these mechanisms has in turn led to several novel strategies for therapeutically enhancing recovery of the injured CNS. Despite this progress, clinical translation remains a challenge for several reasons, including: 1) problems in projecting beneficial outcomes from small animal models to primate systems, 2) a lack of robust improvement in functional outcomes in animal models, and 3) difficulty replicating published reports in the field. Collectively, while the field has seen great progress, reconstructing the exquisite circuitry of the injured human CNS will require yet greater progress in both understanding of basic mechanisms underlying axonal growth and guidance, and testing of optimized therapies in models more predictive of potential human benefit.

DOI: 10.29245/2572.942X/2016/6.1056 View / Download Pdf

Kimbra Kenney, Margalit Haber, Franck Amyot, Cora Davis, Angela Pronger, Carol Moore, Ramon Diaz-Arrastia*

Department of Neurology, Center for Neuroscience and Regenerative Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA

Traumatic cerebral vascular injury (TCVI) is a frequent, perhaps universal, feature after traumatic brain injury (TBI) and may be responsible for some TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature (CMV) is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive microvascular injury in humans and experimental animals, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences Arterial Spin Labeling (ASL), Transcranial Doppler, Near InfraRed Spectroscopy (NIRS), etc. Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for developing novel TBI therapies.

DOI: 10.29245/2572.942X/2016/6.1067 View / Download Pdf

Maria Amelia Chang

Neuro-IFRAH Organization, San Diego, CA, USA

This is a clinical commentary that expands on an initial attempt to classify possible adverse effects (AE) of repeated and long-term use of Botox A (BTX) to manage post-stroke spasticity into three types, local, systemic and subclinical AE. Clinical manifestations of non-local, systemic AE from widespread diffusion of BTX are presented to help clinicians and researchers recognize changes that may develop in post-stroke patients. Subclinical AE of muscle atrophy and bone degradation may hinder return of motor control and increase certain risk factors. Even with increased trend in the use of BTX, very little is written about long term effects of repeated BTX injections for post-stroke spasticity coupled by fewer clinicians who report what they find in actual practice. Although published studies infrequently report AE, it will be an error if it is attributed to an extension of the disease process in stroke.

DOI: 10.29245/2572.942X/2016/6.1054 View / Download Pdf

Barbro H Skogman1*, Johanna Sjöwall2, Per-Eric Lindgren3

1Paediatric clinic, Falun General Hospital and Center for Clinical Research (CKF) Dalarna – Uppsala University, Sweden
2Clinic of Infectious Diseases, Linköping University Hospital and Division of Clinical Immunology, Department of Clinical and Experimental Medicine, University of Linköping, Sweden
3Medical Microbiology, Department of Clinical and Experimental Medicine, University of Linköping, S-581 85 Linköping, Sweden and Microbiological Laboratory, Medical Services, County Hospital Ryhov, Sweden

Commentary on of the publication: “The NeBoP score - a Clinical Prediction Test for Evaluation of Children with Lyme Neuroborreliosis in Europe” BMC Pediatrics (2015) 15:214 (DOI 10.1186/s12887-015-0537-y)

DOI: 10.29245/2572.942X/2016/6.1057 View / Download Pdf

James Giordano1,2*, Kira Becker1,3, John R. Shook4

1Neuroethics Studies Program, Pellegrino Center for Clinical Bioethics, Georgetown University Medical Center, Washington, DC, USA
2Departments of Neurology and Biochemistry, Georgetown University Medical Center, Washington, DC, USA
3Department of Neuroscience, Amherst College, Amherst, MA, USA
4Graduate Program in Science and the Public, University of Buffalo, Buffalo, NY, USA

Neuroethics is a relatively new, yet ever expanding discipline, which focuses on the “neuroscience of ethics” and the “ethics of neuroscience”. In this essay, we discuss the literature describing the “neuroscience of ethics”. Current approaches to employing neuroscientific techniques and tools to elucidate brain processes serving ethical decision making has evolved from prior psychological studies of how and why humans believe and act in ways deemed to be moral. While a number of neuroanatomical pathways have been defined as participatory in certain types of decision-making, it appears that none are exclusively dedicated to moral cognition or actions. Moreover, attempts at enhancing morality through neurological interventions are plagued by differing constructs of what constitutes moral action in various contexts. Herein, we review developments in neuroscientific studies of morality, and present a rational view of the capabilities, limitations and responsibilities that any genuine neuroethical address and discourse should regard.

DOI: 10.29245/2572.942X/2016/6.1062 View / Download Pdf

GJ de Borst*, V.E.C. Pourier

Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands

DOI: 10.29245/2572.942X/2016/6.1058 View / Download Pdf

Gregory D. Arnone1, Matt Wonais2, Andreas Linninger1,3, Ankit I. Mehta1*

1Department of Neurosurgery, University of Illinois at Chicago, Chicago, IL 60612, USA
2University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA
3Department of Bioengineering, The University of Illinois at Chicago, Chicago, IL, USA

DOI: 10.29245/2572.942X/2016/6.1060 View / Download Pdf

Yeu-Shiuan Su1*, Wei-Hsin Sun1,2*

1Department of Life Sciences, National Central University, Jhongli, Taiwan
2Center for Biotechnology and Biomedical Engineering, National Central University, Jhongli, Taiwan

Serotonin [5-hydroxytryptamine (5-HT)] is an inflammatory mediator which contributes to inflammatory pain. We previously demonstrated that 5-HT-induced mechanical hyperalgesia is mediated by 5-HT2B, but not by other 5-HT receptors. Our recent article provided further evidence how 5-HT2B regulates 5-HT-induced mechanical hyperalgesia, and suggested, that 5-HT2Bmediates mechanical hyperalgesia through Gq/11-phospholipase Cβ (PLCβ)-protein kinase Cε (PKCε) pathway. Interestingly, transient receptor potential vanilloid 1 (TRPV1) also involves in 5-HT2B-mediated hyperalgesia. It was the first evidence that 5-HT receptor regulates TRP channel to affect mechanical hyperalgesia. It is a commentary on the recent article that suggests distinct roles of peptidergic (IB4-negative) and non-peptidergic (IB4-positive) nociceptors in regulating 5-HT-induced mechanical hyperalgesia. In IB4-negative neurons, 5-HT2B in response to 5-HT mediates PLCβ-PKCε to regulate TRPV1 function. In IB4-positive neurons, 5-HT2B may control 5-HT3 or other channels to regulate mechanical hyperalgesia.

DOI: 10.29245/2572.942X/2016/6.1055 View / Download Pdf

Vera Clemens, Francesca Regen, Julian Hellmann-Regen*

Charité Universitätsmedizin Berlin, Klinik für Psychiatrie und Psychotherapie, Campus Benjamin Franklin, Germany

Major depression (MDD) is one of the leading global causes of all non-fatal burden of disease. Involving monoaminergic imbalances, but also hormonal, structural and inflammatory alterations, the underlying pathogenesis remains incompletely understood. The antidepressant drug fluoxetine, which may be considered the “prototype” of all selective serotonin reuptake inhibitors (SSRI), appears to affect all of these processes. Interestingly, this is also the case for retinoic acid (RA), the highly potent active metabolite of vitamin A. In this review, we discuss RA signaling as a central mechanism of action – and missing link – for the multiple, pleiotropic effects of fluoxetine in the CNS, suggesting that direct inhibition of CYP-450-mediated RA catabolism by fluoxetine results in increased local concentration, and enhanced paracrine RA signaling in the CNS.

DOI: 10.29245/2572.942X/2016/6.1028 View / Download Pdf

Deepika Rajesh, H. Ian Robins*, Steven P. Howard

K4 CSC, 600 Highland Avenue, University of Wisconsin Paul P Carbone Comprehensive Cancer Center, Madison, WI 53792, USA

The poor prognosis of malignant glioma patients highlights the need to develop low toxicity, tumor specific agents with the ability to synergize with proven efficacious treatment modalities, e.g., ionizing irradiation. This paper investigates the potential of BNP1350 (karenitecin), a topoisomerase I-targeting anticancer agent, and flavopridol a cyclin-dependent kinase inhibitor as radiosensitizers at clinically relevant doses in glioblastoma cell lines. A clonogenic survival and apoptosis assays were performed to test the effect of karenitecin (0.1 nM to 10 nM), flavopridol, (50 nM to 500 nM), radiation (1 Gy to 5.5 Gy) and a combination of radiation and karenitecin or radiation and flavopridol on the glioma cell lines T986 and M059K. Cells were stained for cyclins B and D using antibodies followed by flow cytometry. Propidium Iodide staining was used to reveal the various phases of the cell cycle; cyclin staining in the G0/G1 and G2/M phase of the cell cycle was estimated as the Mean Fluorescence Intensity (MFI) after subtracting the MFI recorded by the isotype controls. Results demonstrated that in irradiated cells, pretreatment with karenitecin induced apoptosis, a transient arrest in the G2/M phase of the cell cycle and increased the expression of cyclin B1. Flavopridol treatment also induced apoptosis and a transient block in the G2/M phase of the cell cycle. The combined effects of karenitecin and flavopridol displayed synergistic effects. The unique radiosensitizing activity of orally administrable karenitecin and flavopridol is consistent with continued investigation of these compounds preclinically, as well as in the clinical setting.

DOI: 10.29245/2572.942X/2016/6.1061 View / Download Pdf

Ramón Martínez-Mármol1, Mercè Salla-Martret2, Daniel Sastre2, Irene Estadella2, Antonio Felipe2*

1Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Australia
2Molecular Physiology laboratory, Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina (IBUB), Universitat de Barcelona, Spain

 The adult mammalian brain contains neural stem cells (NSCs) that generate neurons and glial cells throughout the lifetime of an organism. NSCs reside in at least two germinal epithelium regions of the adult brain, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the hippocampus. Newborn neurons incorporate into the existing functional networks and play important innate and adaptive roles in cognition, behavior and tissue repair1,2. The identity of particular neural stem cells that generate different classes of neurons and glia, as well as the molecular mechanisms that governs this process in vivo, is a subject of extensive research and debate. Epidermal Growth Factor Receptor (EGFR) activation is one of the most important pathways controlling neural stem cell number and self-renewal3,4. On the other hand, the Shaker-type delayed rectifier K+ channel Kv1.3 functions during cell proliferation, differentiation and migration in many cell types5. This channel is expressed in brain progenitor cells where participates in modulating their final fate. This review summarizes the major findings concerning Kv1.3 and neural stem cell modulation, emphasizing the combination of Kv1.3 with EGFR as promising pharmacological targets against autoimmune neuro-degenerative diseases.

DOI: 10.29245/2572.942X/2016/5.1034 View / Download Pdf

Masashi Kanayama1, Mari L. Shinohara2*

1Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA
2Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA

 Abstract Autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS), are characterized by infiltration of pathogenic immune cells in the CNS. Cells infiltrated in the CNS express pro-inflammatory molecules and cause demyelination. The direct impact of lung immune responses was not previously considered in the pathogenesis of CNS inflammation. However, it recently became clear that the lung acts as a hub organ of pathogenic T cells that are migrating to the CNS. More recent studies further showed that inflamed lung has a critical impact on autoimmune CNS inflammation. Here, we discuss the contribution of the lung in the pathogenesis of CNS autoimmune diseases based on recent reports.

DOI: 10.29245/2572.942X/2016/5.1049 View / Download Pdf

Eduardo NC Bergamaschi1, Fernanda C Nunes2,3, Victor W de Oliveira3, Alessandra Laitart3, Maria L Benevides3, Jean C Nunes2,3*

1Serviço de Neurologia, Departamento de Clínica Médica, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil.
2Neurodiagnostic Brasil, Diagnósticos em Neuropatologia, Florianópolis, SC, Brazil.
3Division of Neuropathology, Hospital Universitário (HU), UFSC, Florianópolis, SC, Brazil.

 Pain is a common and often disabling symptom in Parkinson’s disease (PD) which has received increasing attention in recent years. Headache represents a common form of pain among the general population, but there are few studies on this symptom in PD. In 2014, our group reported a lower prevalence of headache in PD patients compared to the general population, as well as an association between the predominant side of headache and the side of initial motor signs of PD. Since then, there has been few new data on the specific issue of headache in PD patients, though several recent studies have contributed to the understanding of pain in PD, both in terms of clinical and pathophysiological aspects, including new observations on pain association with side of motor symptom onset. Here, we review those studies, and re-discuss our own findings in comparison to the current information available. A better comprehension of pain physiology in PD could facilitate the development of new therapeutic approaches, thus providing a better quality of life for PD patients.

DOI: 10.29245/2572.942X/2016/5.1051 View / Download Pdf

Becker L1, Kutz DF2, Voelcker-Rehage C1*

1Institute of Human Movement Science and Health, Sports Psychology, Technische Universität Chemnitz, Thüringer Weg 11, 09126 Chemnitz, Germany
2Institute of Human Movement Science and Health, Theory and Practice of Sports, Technische Universität Chemnitz, Thüringer Weg 11, 09126 Chemnitz, Germany

DOI: 10.29245/2572.942X/2016/5.1044 View / Download Pdf

Robert C.A.M. van Waardenburg*

Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham AL, USA

 Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H493R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex. The ATM kinase activates proteins early on in response to DNA damage. Tdp1-/- and Atm-/- mice exhibit accumulation of DNA topoisomerase I-DNA covalent complexes (TOPO1-cc) explicitly in neuronal tissue during development. TDP1 resolves 3’- and 5’-DNA adducts including trapped TOPO1-cc and TOPO1 protease resistant peptide-DNA complex. ATM appears to regulate the response to TOPO1-cc via a noncanonical function by regulating SUMO/ubiquitin-mediated TOPO1 degradation. In conclusion, TDP1 and ATM are critical factors for neuronal cell viability via two independent but cooperative pathways.

DOI: 10.29245/2572.942X/2016/5.1048 View / Download Pdf