An ancient conserved role for prion protein in learning and memory

Abstract

The misfolding of cellular prion protein (PrPC) to form PrP Scrapie (PrPSc) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrPC function in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrPC in healthy brains is key. Disrupting PrPC in mice has led to a myriad of controversial functions that sometimes map onto disease symptoms, including a proposed role in memory or learning. Intriguingly, PrPC interaction with amyloid beta (Aβ) oligomers at synapses has also linked its function to Alzheimer's disease and dementia in recent years. We set out to test the involvement of PrPC in memory using a disparate animal model, the zebrafish. Here we document an age-dependent memory decline in prp2−/− zebrafish, pointing to a conserved and ancient role of PrPC in memory. Specifically, we found that aged (3-year-old) prp2−/− fish performed poorly in an object recognition task relative to age-matched prp2+/+ fish or 1-year-old prp2−/− fish. Further, using a novel object approach (NOA) test, we found that aged (3-year-old) prp2−/− fish approached the novel object more than either age-matched prp2+/+ fish or 1-year-old prp2−/− fish, but did not have decreased anxiety when we tested them in a novel tank diving test. Taken together, the results of the NOA and novel tank diving tests suggest an altered cognitive appraisal of the novel object in the 3-year-old prp2−/− fish. The learning paradigm established here enables a path forward to study PrPC interactions of relevance to Alzheimer's disease and prion diseases, and to screen for candidate therapeutics for these diseases. The findings underpin a need to consider the relative contributions of loss- versus gain-of-function of PrPC during Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies.

Prion gene paralogs are dispensable for early zebrafish development and have nonadditive roles in seizure susceptibility

“…We recently engineered mutations of prp2 and were surprised to observe that the fish developed normally, with phenotypes that included deeply conserved roles in NMDA receptor dysregulation, learning/memory, and seizure susceptibility (16,27). This contrasted several works (including our own) using prion knockdown to produce dramatic early defects and suggested that PrP C is required for embryonic development (16,22,28).…”

“…Indeed that notion was partially supported by examining the impact of PrP C loss on NMDA receptors, wherein the kinetics of channel closing were pushed toward hyperexcitability in both fish and mice (16). Further roles for PrP C at the synapse appear to be shared between mice and zebrafish, because its loss in either species leads to deficits in learning and memory (27,71).…”

“…RFLP to detect fish heterozygous and homozygous for the ua5001 allele-For ease of genotyping fish with the prp2 ua5001 allele previously isolated (16), a restriction fragment length polymorphism (RFLP) assay was developed, as reported recently (27). Genomic DNA was amplified using prp2 RFLP primers (Table S2) and then digested with Fast Digest MvaI (ThermoFisher Scientific, catalog no.…”

Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction

“…Although there have been decades of research, a full understanding of the physiological function of PrPc is lacking. Recently, some functions have been attributed to PrPc in the nervous system including neurite outgrowth [ 10 , 11 ], anti-apoptotic roles (during oxidative stress-induced cell death), pro-apoptotic roles (in ER stress) [ 12 , 13 ], Cu 2+ binding [ 14 , 15 ], synaptic plasticity [ 16 ], learning and memory [ 17 ], as well as sleep patterns [ 18 ]. The best strategy to better elucidate the physiological functions of PrPc is to identify and characterize its interacting protein partners because these interactions are most likely to be parts of physiological pathways in which PrPc plays a role ( Figure 1 ).…”

Show Me Your Friends and I Tell You Who You Are: The Many Facets of Prion Protein in Stroke

“…The causes of PrP misfolding include sporadic conformational change, genetic mutations, or contact with infectious material already containing misfolded seeds leading to PrPSc-templated conversion of PrPC [ 20 ]. PrPC is very well conserved in mammals [ 21 , 22 ], and some domains (i.e., the C-terminal domain) are even preserved from fishes to mammals, probably indicating an important physiological function [ 23 , 24 , 25 , 26 ]. However, a clearly defined function is not yet specified but several, such as a role in regulating synaptic activity, as a receptor for toxic oligomers, as a regulator of neuritogenesis, and in contributing to peripheral myelination (reviewed in [ 27 ].…”