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New mode of propagation identified for variant Creutzfeldt-Jakob disease

In an article published in Acta Neuropathologica, researchers from SEPIA (CEA-Jacob) reported the discovery of a new mode of prion propagation from a localized contamination.

Published on 16 November 2020

Prion diseases are a group of rare pathologies characterized by central nervous system degeneration and the formation of infectious aggregates of misfolded prion protein (PrP or PrPd for the diseased variant).

The transmission of prion diseases from one individual to another has been a subject of study for many years now. Work done on non-human primate models has shown that prion diseases can be transmitted by inoculation, an observation that led to the concept and terminology of transmissible spongiform encephalopathies. These diseases evolve rapidly, inevitably cause death and have no current treatments. In humans, prion diseases may be sporadic (e.g., Creutzfeldt-Jakob disease (CJD), the most frequently encountered form), familial/genetic (associated with a mutation in the gene coding the prion protein) or acquired. For these latter, transmission may be iatrogenic (caused by certain medical interventions) or ingestive (caused by consuming contaminated animal products such as those from cows with bovine spongiform encephalopathy (BSE)) and may lead to variant Creutzfeldt–Jakob disease (vCJD) in humans.

In acquired forms due to "peripheral" contamination (oral or intravenous routes), PrPds replicate first in the lymphoid organs (lymph node, spleen) before spreading to the central nervous system. In an article published in Acta Neuropathologica, researchers from the Unit of Prion Disorders and Related Infectious Agents (SEPIA) brought to light a formerly unidentified mode of prion propagation in a non-human primate model. In the study, the team incised a finger of a macaque and injected therein a vCJD/BSE inoculation. After seven years of silent incubation, the first behavioral and neurological symptoms were observed. Biochemical analyses confirmed the presence of PrPd in the macaque's central nervous system and histopathological analyses the presence of lesions specific to prion diseases and a signature specific to vCJD.

Immunostaining showed PrPd in the dorsal root ganglia of the nerve path serving the injection site (median and ulnar nerves), and furthermore in the associated satellite and Schwann (glial cells responsible for axon myelination) cells. In contrast, the lymphoid organ involvement seen in subjects infected via oral or intravenous routes was not present in the SEPIA team's study. The researchers thus proposed a hypothesis of strictly neuronal propagation upon contamination of highly innervated zones. In this mode, PrPds initially propagate slowly, from Schwann cell to Schwann cell along the involved nerve, before attaining the dorsal root ganglia where the infection becomes neuronal and thereafter moves more rapidly within the central nervous system.

Human and experimental neuropathology studies have already led to descriptions of "adaxonal" (close to an axon) lesions, but the present work shines a new light on the immunopathological involvement of Schwann cells in prion diseases.

Consequently, the results of the SEPIA team suggest the possibility of direct neuroinvasion when contamination occurs in highly innervated regions like the fingers, and underline the need for strict procedures to avoid such a contamination in humans.

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