Nobel prize and the history of blood transfusion Muller, J-Y
Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine,
09/2019, Letnik:
26, Številka:
3
Journal Article
Les maladies à prions ou encéphalopathies spongiformes transmissibles (EST) sont des maladies humaines et animales transmissibles naturellement ou expérimentalement avec une longue durée d’incubation ...et une évolution fatale sans rémission. La nature exacte de l’agent transmissible reste discutée mais l’absence de structure évoquant un micro-organisme conventionnel a conduit Stanley B. Prusiner à émettre l’hypothèse qu’il pourrait s’agir d’une protéine infectieuse (proteinaceous infectious particle ou prion). Le prion serait la forme anormale d’une protéine normale, la PrP cellulaire (PrPc) qui va changer de conformation spatiale et être convertie en protéine prion scrapie (PrPsc) ayant des propriétés de résistance partielle aux protéases, d’agrégation et d’insolubilité dans les détergents. Les EST ne s’accompagnent d’aucune réaction inflammatoire ou immunitaire et se caractérisent par les lésions cérébrales associant spongiose, raréfaction neuronale, gliose astrocytaire et accumulation de la PrPsc pouvant prendre l’aspect de plaques amyloïdes. Si le lien entre l’accumulation de PrPsc et la survenue des lésions est discuté, la présence de PrPsc est constante au cours des EST et sa mise en évidence est nécessaire au diagnostic de certitude. Même si elles restent des maladies rares (2 cas par million), l’identification du kuru, à la fin des années 1950, des cas iatrogènes au courant des années 1970 et de la variante de la maladie de Creutzfeldt-Jakob (MCJ) au milieu des années 1990 expliquent l’intérêt pour ces maladies, mais aussi les craintes qu’elles peuvent faire peser sur la santé publique. Elles demeurent un modèle passionnant de recherche car elles appartiennent à la fois au groupe des maladies neurodégénératives avec accumulation de protéines (MCJ sporadique), au groupe des maladies transmissibles (MCJ iatrogènes, variante de la MCJ) mais aussi au groupe des affections génétiques de transmission mendélienne dominante (MCJ génétiques, syndrome de Gerstmann-Straussler-Scheinker, insomnie fatale familiale).
Prion diseases or transmissible spongiform encephalopathies (TSEs) are human and animal diseases naturally or experimentally transmissible with a long incubation period and a fatal course without remission. The nature of the transmissible agent remains debated but the absence of a structure evoking a conventional microorganism led Stanley B. Prusiner to hypothesize that it could be an infectious protein (proteinaceous infectious particle or prion). The prion would be the abnormal form of a normal protein, cellular PrP (PrPc) which will change its spatial conformation and be converted into scrapie prion protein (PrPsc) with properties of partial resistance to proteases, aggregation and insolubility in detergents. No inflammatory or immune response are detected in TSEs which are characterized by brain damage combining spongiosis, neuronal loss, astrocytic gliosis, and deposits of PrPsc that may appear as amyloid plaques. Although the link between the accumulation of PrPsc and the appearance of lesions remains debated, the presence of PrPsc is constant during TSE and necessary for a definitive diagnosis. Even if they remain rare diseases (2 cases per million), the identification of kuru, at the end of the 1950s, of iatrogenic cases in the course of the 1970s and of the variant of Creutzfeldt-Jakob disease (CJD) in the mid-1990s explain the interest in these diseases but also the fears they can raise for public health. They remain an exciting research model because they belong both to the group of neurodegenerative diseases with protein accumulation (sporadic CJD), to the group of communicable diseases (iatrogenic CJD, variant of CJD) but also to the group of genetic diseases with a transmission Mendelian dominant (genetic CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia).
Creutzfeldt-Jakob hastalığı (CJH); bilişsel ve ruhsal durumda bozulma,
serebellar ataksi, miyoklonik hareketler ve görme kaybı bulguları ile
ortaya çıkan bir prion hastalığıdır. Hızla ilerleyerek ...ölüme sebep olması
nedeni ile diğer hastalıklardan ayırt edilmesi önemlidir. Kesin tanı
postmortem otopsi sonucunda alınan beyin örneğinin, histopatolojik
incelemesi ile konulur. Hastaların farklı klinik özelliklerle başvurması
hastalığın tanınmasını güçleştirmektedir. Birinci olgu; elli yaşında erkek,
üç aydır olan ajitasyon, bilinç bozukluğu ve istemsiz hareketler nedeni ile
kliniğe yatırıldı. İkinci olgu; yetmiş yaşında erkek unutkanlık, konversiyon
bozukluğu şeklinde total görme kaybı ve ataksi yakınması ile başvurdu.
Manyetik rezonans görüntüleme (MRG) ve elektroensefalografi
(EEG) ile tanısal olarak desteklenen hastanın beyin omurilik sıvısı
incelemesinde 14.3.3 protein yüksekliği belirlendi. Sonuçta hızlı gelişen
nöropsikiyatrik hastalık özellikleri olan bu olgularda prion hastalığı
düşünüldü. Bu hastalarda tekrarlanan EEG ve MRG incelemesi tanısal
açıdan oldukça faydalıdır. Etkin tedavisi olmasa da koruyucu önlemler
açısından hastalığın tanınması oldukça önemlidir.
La transconformation (transmission de la conformation anormale) de protéines est un nouveau paradigme des maladies neurodégénératives, du vieillissement cérébral, de la myosite à inclusions ...sporadique, du diabète de type 2… Le repliement anormal se transmet d’une protéine à l’autre, puis d’une cellule à l’autre, comme le font les Prions. Dans le système nerveux, il survient dans quelques neurones et suit la direction du flux axonal ou la voie inverse. On distingue schématiquement trois types de propagation neuro-anatomique : « centripète » (synucléinopathie de la maladie de Parkinson où les lésions progressent des nerfs péricardiques, des plexus entériques… vers le méso et le néocortex ; la biopsie cutanée « fenêtre ouverte sur le cerveau » peut donc s’avérer un outil diagnostique), « centrifuge », du cortex vers le tronc cérébral (Aβ du vieillissement et la maladie d’Alzheimer, SOD et TDP-43 phosphorylée de la sclérose latérale amyotrophique) ou enfin « central » intéressant les réseaux neuronaux encéphaliques (TDP-43 de la variante comportementale de la démence frontotemporale). Les peptides Aβ et les protéines tau anormales de la maladie d’Alzheimer, longtemps considérés « centraux », sont aussi extracérébraux. L’exploration des mécanismes de la transconformation : intervention de protéines chaperones, formation de molécules labiles très toxiques (oligomères ?)… laisse entrevoir de multiples possibilités thérapeutiques.
Protein misfolding and spreading (“transconformation”) are being better understood. Described in Prions diseases, this new paradigm in the field of neurodegenerative disorders and brain aging also implies sporadic inclusion myositis, type 2 diabetes, some cancers, sickle cell disease… Misfolding is transmitted from a protein or peptide to a normally folded one. Often associated with a stress of the endoplasmic reticulum, it may spread along the neurites, following anterograde or retrograde axonal transport. In the central nervous system, it occurs in a few cells and there is invasion of adjacent cells by cell-to-cell spread. Three varieties of protein misfolding occur along neuroanatomical pathways. It can be a ‘centripetal’ process. The synucleinopathy of Parkinson disease has been carefully studied: the changes first occur in cardiac or enteric plexuses… and reach later on the mesencephalon and neocortex. Thus, skin biopsy might prove a diagnostic tool. Protein misfolding may also occur along ‘centrifugal’ pathways, from motor cortex to peripheral motor neurons. Examples are provided by SOD and pTDP-43 in Amyotrophic Lateral Sclerosis. Amyloid β peptide in cerebral aging and Alzheimer's disease also spread from occipital cortex to the brainstem. Lastly, the propagation may remain ‘central’ for TDP-43 in behavioral variant frontotemporal dementia, following only pathways of the encephalic neural network. This has to be confirmed, however, since the spreading of some proteins (such as tau or Aβ peptides) has been considered central for a long time and has proved today to involve extracerebral tissues. The complex mechanisms of protein misfolding, still in analysis, include the involvement of chaperone proteins, the formation of very toxic labile proteins molecules (oligomers?), and provide a number of new therapeutic perspectives.
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