J. Neurochem. (2010) 114, 440–451. Abstract Previous in vitro and in vivo investigations have suggested manganese (Mn2+) may play a role in pathogenesis through facilitating refolding of the normal cellular form of the prion protein into protease resistant, pathogenic isoforms (PrPSc), as well as the subsequent promotion of higher order aggregation of these abnormal conformers. To further explore the role of Mn2+ in pathogenesis, we undertook a number of studies, including an assessment of the disease modifying effects of chelation therapy in a well‐characterized mouse model of prion disease. The di‐sodium, calcium derivative of the chelator, cyclohexanediaminetetraacetic acid (Na2CaCDTA), was administered intraperitoneally to mice inoculated intra‐cerebrally with either high or low‐dose inocula, with treatment beginning early (shortly after inoculation) or late (at the usual mid‐survival point of untreated mice). Analyses by inductively coupled plasma‐mass spectrometry demonstrated brain Mn2+ levels were selectively reduced by up to 50% in treated mice compared with untreated controls, with copper, iron, zinc and cobalt levels unchanged. In mice administered high‐dose inocula, none of the treatment groups displayed an increase in survival although western blot analyses of early intensively treated mice showed reduced brain PrPSc levels; mice infected using low‐dose inocula however, showed a significant prolongation of survival (p = 0.002). Although our findings support a role for Mn2+ in prion disease, further studies are required to more precisely delineate the extent of pathogenic involvement.

No abstract

The amyloid precursor–like protein 2 (APLP2) molecule is a type I transmembrane protein that is crucial for survival, cell‐cell adhesion, neuronal development, myelination, cancer metastasis, modulation of metal, and glucose and insulin homeostasis. Moreover, the importance of the amyloid precursor protein (APP) family in biology and disease is very well known because of its central role in Alzheimer disease. In this study, we determined the crystal structure of the independently folded E2 domain of APLP2 and compared that with its paralogues APP and APLP2, demonstrating high overall structural similarities. The crystal structure of APLP2 E2 was solved as an antiparallel dimer, and analysis of the protein interfaces revealed a distinct mode of dimerization that differs from the previously reported dimerization of either APP or APLP1. Analysis of the APLP2 E2 metal binding sites suggested it binds zinc and copper in a similar manner to APP and APLP1. The structure of this key protein might suggest a relationship between the distinct mode of dimerization and its biologic functions.—Roisman, L. C., Han, S., Chuei, M. J., Connor, A. R., Cappai, R. The crystal structure of amyloid precursor‐like protein 2 E2 domain completes the amyloid precursor protein family. FASEB J. 33, 5076–5081 (2019). http://www.fasebj.org

The availability of recombinant prion proteins (recPrP) has been exploited as a model system to study PrP-mediated toxicity, conversion, and infectivity. According to the protein only hypothesis, the central event in the pathogenesis of prion diseases is the conversion of PrP(C) to PrP(Sc). This involves a dramatic increase in beta sheet conformation as PrP(C) is converted to PrP(Sc), and it is widely believed that this conformational change affects the as-yet undefined function of PrP(C). Although there are many methods available to monitor for the changes in the structural makeup of PrP mutants and oligomers formed with respect to disease relevance, circular dichroism is one of the most popular methods used. In this chapter, we discuss the fundamental principles of circular dichroism and its current role and applications in prion disease research.