The current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the ...pathologic prion protein (PrP
Sc
), defining two major PrP
Sc
types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (
PRNP
). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrP
Sc
type and codon 129 genotype on
PRNP
mutated allele, each showing distinctive histopathological characteristics, irrespectively of the
PRNP
associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrP
Sc
type of intermediate size (“i”) between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a “thickened” synaptic pattern in E200K carriers, cerebellar “stripe-like linear granular deposits” in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M”i”). A few isolated cases linked to rare
PRNP
haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrP
Sc
significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis.
Human mini-brains (MB) are cerebral organoids that recapitulate in part the complexity of the human brain in a unique three-dimensional in vitro model, yielding discrete brain regions reminiscent of ...the cerebral cortex. Specific proteins linked to neurodegenerative disorders are physiologically expressed in MBs, such as APP-derived amyloids (Aβ), whose physiological and pathological roles and interactions with other proteins are not well established in humans. Here, we demonstrate that neuroectodermal organoids can be used to study the Aβ accumulation implicated in Alzheimer's disease (AD). To enhance the process of protein secretion and accumulation, we adopted a chemical strategy of induction to modulate post-translational pathways of APP using an Amyloid-β Forty-Two Inducer named Aftin-5. Secreted, soluble Aβ fragment concentrations were analyzed in MB-conditioned media. An increase in the Aβ42 fragment secretion was observed as was an increased Aβ42/Aβ40 ratio after drug treatment, which is consistent with the pathological-like phenotypes described in vivo in transgenic animal models and in vitro in induced pluripotent stem cell-derived neural cultures obtained from AD patients. Notably in this context we observe time-dependent Aβ accumulation, which differs from protein accumulation occurring after treatment. We show that mini-brains obtained from a non-AD control cell line are responsive to chemical compound induction, producing a shift of physiological Aβ concentrations, suggesting that this model can be used to identify environmental agents that may initiate the cascade of events ultimately leading to sporadic AD. Increases in both Aβ oligomers and their target, the cellular prion protein (PrPC), support the possibility of using MBs to further understand the pathophysiological role that underlies their interaction in a human model. Finally, the potential application of MBs for modeling age-associated phenotypes and the study of neurological disorders is confirmed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Exposure of human populations to bovine spongiform encephalopathy through contaminated food has resulted in <250 cases of variant Creutzfeldt-Jakob disease (vCJD). However, more than 99% of vCJD ...infections could have remained silent suggesting a long-term risk of secondary transmission particularly through blood. Here, we present experimental evidence that transfusion in mice and non-human primates of blood products from symptomatic and non-symptomatic infected donors induces not only vCJD, but also a different class of neurological impairments. These impairments can all be retransmitted to mice with a pathognomonic accumulation of abnormal prion protein, thus expanding the spectrum of known prion diseases. Our findings suggest that the intravenous route promotes propagation of masked prion variants according to different mechanisms involved in peripheral replication.
Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective ...measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.
History of Pick's disease Mikol, Jacqueline
Clinical neuropathology,
07/2020, Letnik:
39, Številka:
4
Journal Article
Recenzirano
After a short summary of Arnold Pick's biography, the history of how Pick's disease (PiD) was reported is presented, from its clinical symptoms to its molecular characterization. The macroscopic ...description of frontotemporal atrophy by Pick is recounted followed by a description of the histological lesions observed by Alzheimer and the progressive characterization of the disease. The subsequent diagnosis has since relied on ultrastructural findings as well as immunohistochemical and biochemical techniques. The discovery of the role of the microtubule-associated τ-protein, encoded by chromosome 17, more specifically of the 3R isoform, has led to the inclusion of PiD in the 3R tauopathies. Today, both sporadic and familial PiDs, including the more frequent behavioral form, are considered as frontotemporal dementias. Experimental models have reproduced some of the lesions but the prion-like hypothesis concerning PiD has not, as yet, been proven.
The presence of prion infectivity in the blood of patients affected by variant Creutzfeldt-Jakob disease (v-CJD), the human prion disease linked to the bovine spongiform encephalopathy (BSE), poses ...the risk of inter-human transmission of this fatal prion disease through transfusion. In the frame of various experiments, we have previously described that several cynomolgus macaques experimentally exposed to prion-contaminated blood products developed c-BSE/v-CJD, but the vast majority of them developed an unexpected, fatal disease phenotype focused on spinal cord involvement, which does not fulfill the classical diagnostic criteria of v-CJD. Here, we show that extensive analyses with current conventional techniques failed to detect any accumulation of abnormal prion protein (PrP
) in the CNS of these myelopathic animals, i.e., the biomarker considered responsible for neuronal death and subsequent clinical signs in prion diseases. Conversely, in the spinal cord of these myelopathic primates, we observed an alteration of their physiological cellular PrP pattern: PrP was not detectable under its full-length classical expression but mainly under its physiological terminal-truncated C1 fragment. This observed disappearance of the N-terminal fragment of cellular PrP at the level of the lesions may provide the first experimental evidence of a link between loss of function of the cellular prion protein and disease onset. This original prion-induced myelopathic syndrome suggests an unexpected wide extension in the field of prion diseases that is so far limited to pathologies associated with abnormal changes of the cellular PrP to highly structured conformations.
History of Pick's disease Mikol, Jacqueline
Revue neurologique,
December 2018, 2018-12-00, Letnik:
174, Številka:
10
Journal Article
Recenzirano
Pick's disease (PiD) is considered as a rare disease and even if it has been the subject of many controversies, its role appears pivotal in the recognition of neurodegenerative diseases of ...non-Alzheimer type. After a short summary of Pick's biography 1 the different periods of individualization of the disease will be briefly reviewed as many books 2–4, theses 5,6 and hundreds of articles have been published on this pathology.
Arnold Pick (1851–1924) was born of German Jewish parents in Gross-Meseritsch in Moravia, at the time controlled by the Austro-Hungarian Empire. After studying medicine, he became successively assistant to T.H. Meynert, Head of the Chair of Psychiatry in Vienna, when C. Wernicke was present, then to C.F.O. Westphal in Berlin. His training included Neurology, Psychiatry and Neuropathology. It has to be noted that he was considered as a Neuropathologist among the Founders of Neurology 7. He came to Prague where he practiced in different psychiatric Departments and was nominated Professor of Psychiatry in 1886. Arnold Pick exchanged his ideas with many international Colleagues. He was well appreciated although he taught in German, even when many students were more fluent in Czech. He retired in 1921 and died of sepsis in 1924.
Arnold Pick published about 350 papers in German or English as well as a textbook on Neuropathology, mostly on apraxia, apragmatism and language disturbances. Between 1892 and 1906, he published five inaugural publications covering localized brain atrophy, the first one entitled “On the relationships between senile atrophy and aphasia” 8. The analysis of these cases has shown that most of them were probably not what nowadays is called PiD; at the time 6 A. Pick did not realize that he was describing a new disease, but he wanted to emphasize the role of a localized atrophy, correlated with an amnestic aphasia. He suggested a degenerative process although, in this period, most dementias were supposed to result from vascular diseases or syphilis. Studying two such cases, A. Alzheimer, using the Bielchowski method, showed the presence of intracellular balls of different size and enlarged cells with an eccentric nucleus, that is the Pick's bodies and the ballooned cells 9 (Fig. 1). Subsequently, many cases of frontal and or temporal atrophy were studied but rejected by many authors because of the non-specific character of the lesions, the absence of senile plaques and Alzheimer neurofibrillary tangles being the unique argument 6. Later on, two papers of importance were published. A. Gans (1923) used the term “Pick's atrophy” which became a source of confusion since it did not indicate the localization 10. K. Onari and H. Spatz (1926) then identified the “Picksche Krankheit” (Pick's disease) in which the fronto-temporal atrophy was the source of cell loss of degenerative origin 11. The clinical symptoms were then described by C. Schneider (1927–1929) 12. The non-specificity was claimed by L. Marchand who described the “Abiotrophic dementias due to Encephalosis” 13.
New studies were performed in France (1962) 2 and in Switzerland (1975) 3. They described a presenile frontal dementia with modifications of behavior and character as well as amnesic aphasia. Atrophy was present in the frontal lobe and in the temporal lobe, the posterior part of the superior gyrus being preserved (knife blade atrophy). Basal ganglia may have been involved as well as the white matter 14. The main histological lesions were upper cortical neuronal loss, gliosis, microvacuolisation, ballooned neurons and argyrophilic inclusions and involvement of the hippocampus 15. Tissot et al. (1975) described three forms:
– temporal atrophy;
– frontal atrophy with only ballooned cells;
– cellular lesions without significant atrophy.
The diagnosis was confirmed by silver staining techniques and electron microscopy studies showing the presence of straight filaments (100 to 120Å in diameter) 16,17 and mixed with a variable number of twisted filaments.
The development of immunochemistry has facilitated the visualization of inclusions using antibodies, firstly against neurofilaments then against the normal and phosphorylated tau protein (family of microtubule-associated proteins). Thus the criteria of the disease seemed well established. However, in 1987, A. Brun described a frontal lobe degeneration (FLD) of non-Alzheimer type, different from PiD 18. D. Neary reported a dementia of the frontal lobe (1988) 19, M.M. Mesulam a primary progressive aphasia (1992) 20, J.S. Snowsden a semantic dementia (1989) 21 and M.A. Neumann a Progressive Subcortical Gliosis (1967) 22. Gradually, the concept of fronto-temporal dementia (FTD) was proposed, including a behavioral variant of FTD, progressive non-fluent aphasia, semantic aphasia and PiD also denominated Pick Complex 4. Furthermore, biochemical studies of Pick brain homogenates showed that they were composed of a major doublet (tau60, tau64) and a minor tau 64 23. They were exclusively composed of 3R-tau, the microtubule binding repeat encoded by exon 10 being absent. As the same tau isoforms were present in Progressive Supranuclear Paralysis and Cortico-Basal Degeneration, a group of 3R-tau diseases was defined including PiD as part of the protein-based classification of neurodegenerative diseases. Based on this result, an exhaustive study using many new antibodies was recently published (2016) 24. Four sequential patterns of pathological tau deposition were identified and tau-positivity of neuropil threads, ramified astrocytic inclusions and oligodendroglial coiled inclusions were demonstrated. The authors proposed a limbic/paralimbic cortices origin of PiD.
Some correlations between clinical and pathological subtypes may be observed, but the clinical presentation does not always predict the underlying pathology. Previous typical forms of PiD have been reported but they do not include tau detection: forms associated with ALS, few familial forms. This led to an interest in an ultrasensitive and selective detection of 3-repeat tau seeding activity in PiD brain and cerebral spinal fluid with RT-Quick r (2017) 25. Perhaps this biomarker will help determine the unknown mechanism of disease development.
Prion diseases are associated with the conformational conversion of the cellular prion protein (PrP(C)) into the pathological scrapie isoform (PrP(Sc)) in the brain. Both the in vivo and in vitro ...conversion of PrP(C) into PrP(Sc) is significantly inhibited by differences in amino acid sequence between the two molecules. Using protein misfolding cyclic amplification (PMCA), we now report that the recombinant full-length human PrP (rHuPrP23-231) (that is unglycosylated and lacks the glycophosphatidylinositol anchor) is a strong inhibitor of human prion propagation. Furthermore, rHuPrP23-231 also inhibits mouse prion propagation in a scrapie-infected mouse cell line. Notably, it binds to PrP(Sc), but not PrP(C), suggesting that the inhibitory effect of recombinant PrP results from blocking the interaction of brain PrP(C) with PrP(Sc). Our findings suggest a new avenue for treating prion diseases, in which a patient's own unglycosylated and anchorless PrP is used to inhibit PrP(Sc) propagation without inducing immune response side effects.
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