Anti-PRNP monoclonal antibody, clone 5121

Patients with pathogenic truncating mutations in the prion gene (PRNP) usually present with prolonged disease courses with severe neurofibrillary tangle and cerebral amyloidosis pathology, but more atypical phenotypes also occur, including those with dysautonomia and peripheral neuropathy. We describe the neurological, cognitive, neuroimaging, and electrophysiological features of a 31-year-old man presenting with an orbitofrontal syndrome, gastrointestinal symptoms, and peripheral neuropathy associated with PRNP Q160X nonsense mutation, with symptom onset at age 27. The mutation was also detected in his asymptomatic father and a symptomatic paternal cousin; several members of prior generations died from early onset dementia. This is the first report of a family affected with the nonsense PRNP mutation Q160X displaying clear autosomal dominant disease in multiple family members and reduced penetrance. This case strengthens the evidence suggesting an association between PRNP truncating mutations and prion systemic amyloidosis. PRNP gene testing should be considered in any patient with atypical dementia, especially with early onset and neuropathy, even in the absence of a family history.

Normally folded prion protein (PrPC) and its functions in healthy brains remain underappreciated compared with the intense study of its misfolded forms (prions, PrPSc) during the pathobiology of prion diseases. This impedes the development of therapeutic strategies in Alzheimer's and prion diseases. Disrupting the zebrafish homologs of PrPC has provided novel insights; however, mutagenesis of the zebrafish paralog prp2 did not recapitulate previous dramatic developmental phenotypes, suggesting redundancy with the prp1 paralog. Here, we generated zebrafish prp1 loss-of-function mutant alleles and dual prp1(-/-);prp2(-/-) mutants. Zebrafish prp1(-/-) and dual prp1(-/-);prp2(-/-) mutants resemble mammalian Prnp knockouts insofar as they lack overt phenotypes, which surprisingly contrasts with reports of severe developmental phenotypes when either prp1 or prp2 is knocked down acutely. Previous studies suggest that PrPC participates in neural cell development/adhesion, including in zebrafish where loss of prp2 affects adhesion and deposition patterns of lateral line neuromasts. In contrast with the expectation that prp1's functions would be redundant to prp2, they appear to have opposing functions in lateral line neurodevelopment. Similarly, loss of prp1 blunted the seizure susceptibility phenotypes observed in prp2 mutants, contrasting the expected exacerbation of phenotypes if these prion gene paralogs were serving redundant roles. In summary, prion mutant fish lack the overt phenotypes previously predicted, and instead they have subtle phenotypes similar to mammals. No evidence was found for functional redundancy in the zebrafish prion gene paralogs, and the phenotypes observed when each gene is disrupted individually are consistent with ancient functions of prion proteins in neurodevelopment and modulation of neural activity.