Unforeseen decrease of full-length prion protein in macaques exposed to prion contaminated blood products
Emmanuel COMOY, Nina JAFFRE, Jérôme DELMOTTE, Jacqueline MIKOL, and Jean Philippe DESLYS Commissariat à l’Energie Atomique, DRF/IBFJ/SEPIA, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France.
Aims: The presence of prion infectivity in blood from patients affected by variant of Creutzfeldt-Jakob disease (v-CJD) questions the risk of its inter-human transmission through transfusion. We have previously described that several cynomolgus macaques experimentally exposed to prion-contaminated blood products developed c-BSE/v-CJD; however, after an exposure to low infectious doses, 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, notably concerning the pathognomonic accumulation of abnormal prion protein. Here we aim to investigate the etiology and physiopathology of this original myelopathy.
Materials and Methods: CNS (brain and spinal cord) samples from myelopathic macaques were tested with different biochemical approaches in comparison to samples derived from either healthy animals or their counterparts exposed to different strains of prion diseases.
Results: Current conventional techniques failed to detect any accumulation of abnormal prion protein (PrPv-CJD) in the CNS of these myelopathic animals. Conversely, in their spinal cord 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.
Conclusions: We here confirm the prion origin of this original syndrome, with a very specific biochemical signature linked to changes in PrP at the level of spinal cord lesions: contrary to what is classically described in prion diseases, host PrP is here altered in a form that is abnormally sensitive to degradation by cellular catabolism. This could provide the first experimental evidence of a link between loss of function of the cellular prion protein and the onset of disease. These observations open up new horizons in the field of prion diseases, which has hitherto been limited to pathologies associated with abnormal changes in cellular PrP towards highly structured conformations, with the possibility of unsuspected prion mechanisms/origins in certain neurodegenerative disorders.
Funded by: Financial support for the study was provided by the French National Research Agency (ANR).
Grant number: ANR-10-BLAN-133001 and BIOTECS2010-BloodSecur
Acknowledgement: We specially thank N. Lescoutra, A. Culeux, V. Durand, E. Correia, C. Durand and S. Jacquin for precious technical assistance
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Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
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Emmanuel COMOY, Nina JAFFRE, Jérôme DELMOTTE, Jacqueline MIKOL, and Jean Philippe DESLYS Commissariat à l’Energie Atomique, DRF/IBFJ/SEPIA, 18 Route du Panorama, 92265 Fontenay-aux-Roses, France.
Aims: The presence of prion infectivity in blood from patients affected by variant of Creutzfeldt-Jakob disease (v-CJD) questions the risk of its inter-human transmission through transfusion. We have previously described that several cynomolgus macaques experimentally exposed to prion-contaminated blood products developed c-BSE/v-CJD; however, after an exposure to low infectious doses, 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, notably concerning the pathognomonic accumulation of abnormal prion protein. Here we aim to investigate the etiology and physiopathology of this original myelopathy.
Materials and Methods: CNS (brain and spinal cord) samples from myelopathic macaques were tested with different biochemical approaches in comparison to samples derived from either healthy animals or their counterparts exposed to different strains of prion diseases.
Results: Current conventional techniques failed to detect any accumulation of abnormal prion protein (PrPv-CJD) in the CNS of these myelopathic animals. Conversely, in their spinal cord 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.
Conclusions: We here confirm the prion origin of this original syndrome, with a very specific biochemical signature linked to changes in PrP at the level of spinal cord lesions: contrary to what is classically described in prion diseases, host PrP is here altered in a form that is abnormally sensitive to degradation by cellular catabolism. This could provide the first experimental evidence of a link between loss of function of the cellular prion protein and the onset of disease. These observations open up new horizons in the field of prion diseases, which has hitherto been limited to pathologies associated with abnormal changes in cellular PrP towards highly structured conformations, with the possibility of unsuspected prion mechanisms/origins in certain neurodegenerative disorders.
Funded by: Financial support for the study was provided by the French National Research Agency (ANR).
Grant number: ANR-10-BLAN-133001 and BIOTECS2010-BloodSecur
Acknowledgement: We specially thank N. Lescoutra, A. Culeux, V. Durand, E. Correia, C. Durand and S. Jacquin for precious technical assistance
Only registered and activated users can see links., Click Here To Register...
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
Only registered and activated users can see links., Click Here To Register...