This page summarises one review, Castle and Gill (2017). About 100,000 of its 328,000 characters were read, and newer work is not covered. The function of PrPC is relevant to therapy design, because PrP-lowering approaches depend on reducing PrPC being tolerated. The review opened here does not test that.
What does PrPC do in the body?
Castle and Gill conclude that the functions best supported by the literature include regulation of myelin maintenance, and processes related to differentiation: proliferation, adhesion and control of cell morphology such as neurite outgrowth. They describe links to circadian rhythm, glucose handling, immune function and iron uptake as intriguing and needing further study.
What do knockout mice show?
Adult-onset demyelination of the peripheral nervous system appears in three knockout lines (Zurich I, Npu and Zurich III). Myelin forms normally before demyelination begins. Expression of PrPC in neurons rescued the phenotype, while expression only in Schwann cells had little effect. No abnormalities of central nervous system myelin were found. The molecular basis of the demyelination is unresolved.
The review cites a 2016 proposal that residues 23 to 33 at the N-terminus of PrPC interact with the receptor GPR126 on Schwann cells and promote cAMP-PKA signalling. The authors note that GPR126-PKA signalling may not be required for myelin maintenance, and suggest that N1, the fragment produced by alpha-cleavage, may mediate the interaction. The mechanism is not settled.
Ataxia in some knockout lines is attributed to ectopic expression of the protein Doppel and not to loss of PrPC.
Which proposed functions are doubted?
| Proposed function | Position in the review |
|---|---|
| Protection against stress | Called unproven. Some serum-deprivation studies used cells that also expressed Doppel. No clear protection during ER stress. Oxidative stress evidence is more convincing but unconfirmed in genetically pure knockout lines. |
| Copper homeostasis | PrPC binds copper in vitro. Relevance in vivo is questioned, and one study found no protection from copper toxicity. |
| Neuronal excitability | Described as a confusing picture. Many findings may reflect genes flanking the Prnp locus in mixed-background mice. |
| Direct pro-survival role | The literature does not provide strong support. Full-length PrPC increased susceptibility to staurosporine in one study, while N1 was protective in another. |
What is unresolved?
The authors list as open which PrPC interactions are direct, how myelin integrity is maintained and whether GPR126 is involved, whether PrPC affects iron homeostasis, whether it protects against stress in genetically pure knockouts, how it affects excitability once flanking-gene effects are controlled, and whether its net effect on Alzheimer’s disease pathogenesis is positive or negative. Whether its role in proliferation and cancer depends on context is also open.
The relation of PrPC to disease is on neurotoxicity, and misfolding is on protein misfolding. See the mechanisms hub and the overview.