Prion-related peripheral neuropathy in sporadic Creutzfeldt-Jakob disease

Abstract

ObjectiveTo assess whether the involvement of the peripheral nervous system (PNS) belongs to the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease (sCJD).MethodsWe examined medical records of 117 sCJDVV2 (ataxic type), 65 sCJDMV2K (kuru-plaque type) and 121 sCJDMM(V)1 (myoclonic type) subjects for clinical symptoms, objective signs and neurophysiological data. We reviewed two diagnostic nerve biopsies and looked for abnormal prion protein (PrPSc) by western blotting and real-time quaking-induced conversion (RT-QuIC) in postmortem PNS samples from 14 subjects.ResultsSeventy-five (41.2%) VV2-MV2K patients, but only 11 (9.1%) MM(V)1, had symptoms or signs suggestive of PNS involvement occurring at onset in 18 cases (17 VV2-MV2K, 9.3%; and 1 MM(V)1, 0.8%) and isolated in 6. Nerve biopsy showed a mixed predominantly axonal and demyelinating neuropathy in two sCJDMV2K. Electromyography showed signs of neuropathy in half of the examined VV2-MV2K patients. Prion RT-QuIC was positive in all CJD PNS samples, whereas western blotting detected PrPSc in the sciatic nerve in one VV2 and one MV2K.ConclusionsPeripheral neuropathy, likely related to PrPSc deposition, belongs to the phenotypic spectrum of sCJDMV2K and VV2 and may mark the clinical onset. The significantly lower prevalence of PNS involvement in typical sCJDMM(V)1 suggests that the PNS tropism of sCJD prions is strain dependent.

Detection of prions in skin punch biopsies of Creutzfeldt–Jakob disease patients

“…With the significant limitation of the low number of tested CJD cases apart from the MM1 group, our results also provide preliminary data about the issue of prion replication outside the CNS and its relationship with prion strains. Interestingly, the lower performance of the Ha PrP substrate with samples from sCJDMM1 subjects is consistent with previous findings from our group indicating that the M1 CJD strain is associated with a lower amount of PrP Sc ‐seeding activity in peripheral tissues in comparison to the V2 strain, linked to the VV2 and MV2K subtypes . Thus, we speculate that the amount of PrP Sc deposition in the skin of sCJDVV2 and MV2K would be well above the limit of detection of the assays and, consequently, sufficient to always seed the reaction with both protocols despite the higher reactivity of the Bv23‐230 substrate, while this would not be the case for the sCJDMM1 samples.…”

“…Ex vivo samples were taken at autopsy, before opening the skull to avoid cross‐contamination with brain tissue. Skin samples were washed three times in cold 1 × PBS, homogenized at 1% (w/v) with gentleMACS Octo Dissociator (Miltenyi BioTec) in cold QuIC buffer (150 mmol/L NaCl, 4 mmol/L EDTA, 1 × PBS, Complete Protease Inhibitor Mixture) and stored at −80°C . 10% (w/v) brain homogenates in cold QuIC buffer with 1% Triton X‐100 of a sCJDVV2 and an AD subject were used as additional positive and negative controls.…”

Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice

“…Mice ablated for PrP (Nishida et al, 1999;Bremer et al, 2010) and goats lacking PrP due to a naturally occurring mutation (Skedsmo et al, 2020) develop a progressive peripheral demyelinating neuropathy, indicating that PrP is involved in myelin maintenance. Although no mutations in the human PRNP gene were found in a study of patients with hereditary neuropathies (Koop et al, 2005), the alteration of PrP or its sequestration in aggregates could explain the development of peripheral neuropathy in patients suffering from Creutzfeldt-Jakob disease (Baiardi et al, 2019). This notion is supported by the occurrence of pronounced peripheral demyelination in certain genetic forms of Creutzfeldt-Jakob disease (Neufeld et al, 1992).…”

Electrophysiological Investigations of Prion Protein Roles in Health and Disease

“…Second, neuronal degeneration is irreversible; attempts to rescue mice that have already undergone neuronal degeneration only prolong the disease progression in the terminal stages to death [53]. In addition, recent studies have reported that at the clinical stage of CJD, the peripheral nerves are also severely demyelinated (Figure 1(6)) [54,55], supporting that therapeutic drug interventions at this stage might be too late. Hence, studies have shifted interests toward understanding changes during the preclinical stage to early onset of clinical signs at which points the neurodegeneration is very minimal and therapeutic interventions have been successful in mice [56].…”