Transmission of vPSPr in macaque: an open gate to prion-like diseases ?
Emmanuel E Comoya, Jacqueline Mikola, Jérôme Delmottea, Wenquan Zoub,c, Jean-Philippe Deslysa
aInstitut François Jacob, Prion Research group, CEA, Fontenay-aux-Roses, France; bInstitute of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China; cDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Aims: A novel form of prion disease initially described in 2008 harbours very original features: reported in less than 50 cases worldwide to date, this prionopathy is characterized by the accumulation of abnormal prion protein with variable protease sensitivity depending on the genotype at PRNP codon 129, and subsequently called vPSPr. Their limited resistance, enforced by an incomplete transmissibility in rodent models, question the infectivity of these borderline prion strains. Moreover, their clinical expressions are often evocative of other neurodegenerative diseases (whose transmissibilities are also currently challenged) like Alzheimer’s disease, fronto-temporal dementia or even amyotrophic lateral sclerosis, and concomitant deposition of other prion-like proteins is frequently reported. We aimed to assess the transmissibility of vPSPr cases in cynomolgus macaque, a model reputed as highly relevant of the human situation according to its close phylogeny.
Materials and Methods: Cynomolgus macaques were intracerebrally inoculated with brain samples issued from 1 M/M and 1 M/V vPSPr case respectively, and kept under surveillance throughout their incubation periods. At the onset of clinical signs, extensive histological, immunohistochemical and biochemical analyses were performed according to the techniques previously used on primates in our previous studies.
Results: Whereas the macaque exposed to M/M vPSPr inoculum remains healthy 14 years post-exposure, the macaque exposed to M/V vPSPr inoculum developed unusual neurological and behavioural disturbances after 8.5 years of silent incubation. The expected hallmarks of vPSPr were observed in this animal, including spongiform change and abnormal PrP depositions under different forms. Unexpectedly, we also observed massive Aβ deposits in this mid-aged (13 years) macaque, a unique situation within our cohort of more than 50 over-ten years-old macaques, in which Aβ deposits may occur after 20 years of age but with different features, including co-staining with PrP, than in this animal.
Conclusions: The physiopathological mechanisms underlying the presence of Aβ deposits in both the brain of this animal recipient and its human donor remains to be elucidated. It may be either evocative of a concomitant presence of an age-related, but de facto transmissible, Aβ pathology with vPSPr in the donor patient, or a specific feature of vPSPr. At a time where the transmissibility of prion-like diseases is more than ever under question, this latter hypothesis would place these uncommon prionopathies at the intersection between prion and Alzheimer’s disease, and maybe other neurodegenerative diseases as ALS and synucleinopathies according to the concomitant prion-like depositions described in some vPSPr patients.
Funding: This study has been performed on internal funding of the laboratory.
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55. Experimental Transmission of Protease Sensitive Prionopathy (VPSPr) to Nonhuman Primates
Jacqueline Mikola, Wenquan Zouc,b, Jérôme Delmottea, Jean-Philippe Deslysa, Emmanuel Comoya
aInstitut François Jacob, Prion Research group, CEA, Fontenay-aux-Roses, France; bInstitute of Neurology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China; cDepartment of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
Aim: Transmission is one of the main characteristics of prion diseases. However, VPSPr, which is now presumed to be the sporadic form of the genetic CJD V180I, is incompletely, if any, transmissible in humanized mice, and transmission in bank voles ‘does not replicate the complex VPSPr-PrPd profile’ (Nonno). We strenghtened the panel of experimental transmission of this uncommon prion strain with cynomolgus macaque, considered a relevant model of human prion diseases.
Material and methods: Transmission was performed in two cynomolgus macaques (PrP MM genotype at codon 129). The animal exposed to the brain of a 75 years-old MV patient developed clinical symptoms after 8.5 years of silent incubation. Euthanasia was performed 4 months later for humane reasons. The other animal is still asymptomatic 14 years after exposure to the brain of a MM patient (68 years).
Subsequently, secondary transmission to transgenic mice overexpressing macaque PrP were conducted.
Histological and biochemical studies were performed as previously published.
Results: The known clinical data of the MV patient were limited to executive dysfunction and unsteady gait.
The MV VPSPr-exposed macaque presented several episodes of self-aggression, first focused on his left leg, which extended to the whole hindquarters. Abnormalities of both hind limbs sensitive conduction were recorded.
Among our different analyses, neuropathological examination showed a spongiform change diffuse in the grey matter with a special profile, associated to a reactive astrocytosis and massive neuronal vacuolation, particularly in the rarefied Purkinje cells. Abnormal PrPd consisted of a diffuse background of thin synaptic deposits mixed with mini aggregates (dots) and some small cortical fussy fibrillar plaques, not preserved after proteolysis, and never observed in primates exposed to other prion strains. At the opposite there was no granules or micro-plaques in the cerebellum although they were noted in the donor patient.
Three other facts must be emphasized: i/ the presence of massive amyloid deposits in the neocortex but not in the hippocampus, except the subiculum more or less associated to PrPd. ii/ the negativity of the staining with AT8, AT100, cytoplasmic TDP43. iii/ the inflammatory reaction observed in the lumbar dorsal root ganglia which may be correlated with the peripheral itching of the legs.
Conclusion: Conversely to classical prion transmission in primate, neuropathology exemplified here a tiny specific pattern of PrPd deposits reminiscent of VPSPr in human. Our observations in primate and secondary in mice sustain the transmissibility of (at least MV) vPSPr-related prion strain which extends the field of classical prion diseases.
Funding: This study has been performed on internal funding of the laboratory.
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https://www.tandfonline.com/doi/full/10.1080/19336896.2024.2424058
