II Congrés Internacional sobre Traducció : abril 1994 : actes

Machine learning-based approach unravels distinct pathological signatures induced by patient-derived α-synuclein seeds in monkeys. Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)-rich protein aggregates [termed "Lewy bodies" (LBs)], is a well-established characteristic of Parkinson's disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneratio

Post translational changes to α-synuclein control iron and dopamine trafficking : a concept for neuron vulnerability in Parkinson's disease

Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high α-synuclein (α-syn) and iron content. α-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to α-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of α-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of α-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for α-syn aggregation. The proposition highlights a connection between α-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease

Loss of Metal Ions, Disulfide Reduction and Mutations Related to Familial ALS Promote Formation of Amyloid-Like Aggregates from Superoxide Dismutase

Mutations in the gene encoding Cu-Zn superoxide dismutase (SOD1) are one of the causes of familial amyotrophic lateral sclerosis (FALS). Fibrillar inclusions containing SOD1 and SOD1 inclusions that bind the amyloid-specific dye thioflavin S have been found in neurons of transgenic mice expressing mutant SOD1. Therefore, the formation of amyloid fibrils from human SOD1 was investigated. When agitated at acidic pH in the presence of low concentrations of guanidine or acetonitrile, metalated SOD1 formed fibrillar material which bound both thioflavin T and Congo red and had circular dichroism and infrared spectra characteristic of amyloid. While metalated SOD1 did not form amyloid-like aggregates at neutral pH, either removing metals from SOD1 with its intramolecular disulfide bond intact or reducing the intramolecular disulfide bond of metalated SOD1 was sufficient to promote formation of these aggregates. SOD1 formed amyloid-like aggregates both with and without intermolecular disulfide bonds, depending on the incubation conditions, and a mutant SOD1 lacking free sulfhydryl groups (AS-SOD1) formed amyloid-like aggregates at neutral pH under reducing conditions. ALS mutations enhanced the ability of disulfide-reduced SOD1 to form amyloid-like aggregates, and apo-AS-SOD1 formed amyloid-like aggregates at pH 7 only when an ALS mutation was also present. These results indicate that some mutations related to ALS promote formation of amyloid-like aggregates by facilitating the loss of metals and/or by making the intramolecular disulfide bond more susceptible to reduction, thus allowing the conversion of SOD1 to a form that aggregates to form resembling amyloid. Furthermore, the occurrence of amyloid-like aggregates per se does not depend on forming intermolecular disulfide bonds, and multiple forms of such aggregates can be produced from SOD1

Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and $^{123}$iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.The DLB Consortium meeting was organized by the Mayo School of Continuous Professional Development (MSCPD) and supported by Acadia Pharmaceuticals, Alzheimer’s Association, Axovant Sciences, Banner Health, GE Healthcare, the Lewy Body Dementia Association, the Lewy Body Society, Lundbeck, the National Institute on Aging, the National Institute on Neurologic Disease and Stroke, and an NIH grant (R13 NS095618). Kathy Fuqua, Julie Reed, and colleagues at the MSCPD provided administrative support to the consortium meeting in Fort Lauderdale. I.G.M., D.B., J.-P.T., J.A., and A.T. receive support from the UK NIHR Biomedical Research Centre awarded to the Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. Travel grant support was provided by the Alzheimer’s Research UK ARUK NE Network Centre. B.F.B., D.W.D., K.K., and T.J.F. are supported by the NIH (P50-AG016574) and the Mangurian Foundation for Lewy Body Research. G.H. is a senior principal research fellowship holder from the National Health and Medical Research Council of Australia (1079679). D.A. is a Royal Society Wolfson Research Merit Award Holder and thanks the Wolfson Foundation and the Royal Society for their support. C.G.B. thanks the Maudsley BRC for Mental Health and BRU dementia for supporting his involvement in the work. A.C.-P. receives research support from the NIH (RO1 NS082265, UO1 NS082134, P50 NS053488), the Burroughs Wellcome Fund, the Alzheimer’s Association/Michael J. Fox Foundation/Weston Biomarkers Across Neurodegenerative Disease initiative, and the Pechenik Montague Award Fund. D.f. acknowledges support from NIHR Programme Grants for Applied Research (RP-PG-0610-10100 SHAPED). O.E.-A. acknowledges support for OE laboratory from the Michael J. Fox Foundation for Parkinson’s Research (New York). S.N.G. receives support from R21 NS 090243 and the National Parkinson’s Foundation. O.A.R. is supported through the Mayo Clinic: A Morris K. Udall Parkinson’s Disease Research Center of Excellence (NINDS P50 NS072187), NINDS R01 NS078086, the Michael J. Fox Foundation for Parkinson’s Research, the Mayo Clinic AD and Related Dementias Genetics Program, and The Little Family Foundation. A.S.’s work is supported by the Intramural Research Program of the National Institute on Aging, Department of Health and Human Services. D.T. acknowledges the work of Cyrus Zabetian, MD, and Ignacio Mata, PhD, from VA Puget Sound Health Care System. J.Q.T. and V.M.Y.L.’s contributions were supported in part by a P50 NS053488 Morris K. Udall Parkinson’s Disease Research Center of Excellence grant from NINDS. P.T. acknowledges support from the Italian Ministry of Health “Ricerca Corrente.” M.Y. acknowledges support from the Japan Foundation for Neuroscience and Mental Health