[citation needed] PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice.

Signal sequences in the amino- and carboxy- terminal ends are removed posttranslationally, resulting in a mature length of 208 amino acids.

[citation needed] PrPSc is a conformational isoform of PrPC, but this orientation tends to accumulate in compact, protease-resistant aggregates within neural tissue.

Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrPC is caused by the presence and interaction with PrPSc.

[26] Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSc and cytotoxicity.

[29] Initial attempts produced two strains of PrP-null mice that show no physiological or developmental differences when subjected to an array of tests.

[16] As the null mice age, a marked loss of Purkinje cells in the cerebellum results in decreased motor coordination.

[11] Fatal familial insomnia is thought to be the result of a point mutation in PRNP at codon 178, which corroborates PrP's involvement in sleep-wake cycles.

A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV.

The lack of immunoresponse to transmissible spongiform encephalopathies (TSE), neurodegenerative diseases caused by prions, could stem from the tolerance for PrPSc.

[49] PrP-null mice provide clues to a role in muscular physiology when subjected to a forced swimming test, which showed reduced locomotor activity.

[16] Given the diversity of interactions, effects, and distribution, PrP has been proposed as dynamic surface protein functioning in signaling pathways.

The abnormal protein PrPSc accumulates in the brain and destroys nerve cells, which leads to the mental and behavioral features of prion diseases.

[55] PrPC protein is one of several cellular receptors of soluble amyloid beta (Aβ) oligomers, which are canonically implicated in causing Alzheimer's disease.

[56] The precise mechanism of soluble Aβ oligomers directly inducing neurotoxicity is unknown, and experimental deletion of PRNP in animals has yielded several conflicting findings.

When Aβ oligomers were injected into the cerebral ventricles of a mouse model of Alzheimer's, PRNP deletion did not offer protection, only anti-PrPC antibodies prevented long-term memory and spatial learning deficits.

In the case of direct injection of Aβ oligomers into the hippocampus, PRNP-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of synaptic plasticity.

[56][58] It was further found that Aβ-oligomers bind to PrPC at the postsynaptic density, indirectly overactivating the NMDA receptor via the Fyn enzyme, resulting in excitotoxicity.

[57] Soluble Aβ oligomers also bind to PrPC at the dendritic spines, forming a complex with Fyn and excessively activating tau, another protein implicated in Alzheimer's.

[56] Of note, the deletion of PRNP in both APPswe and SEN1dE9, two other transgenic models of Alzheimer's, attenuated the epilepsy-induced death phenotype seen in a subset of these animals.

[56] Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer's.

[59] Variant V allele carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer's compared to the methionine homozygote (MM).

[56] A point mutation on codon 102 of PRNP at least in part contributed to three separate patients' atypical frontotemporal dementia within the same family, suggesting a new phenotype for Gerstmann–Sträussler–Scheinker syndrome.