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Prion Protein Mutation Database

PrP Function

The precise physiological function of PrPC is unknown. It is ubiquitously expressed throughout the brain and is enriched at the pre- and post-synaptic membranes, where it is thought to play a critical role in neuronal maintenance and neuroprotection1-2. Additionally, the well-documented ability of PrPC to coordinate Cu2+ and Zn2+ cations 3-4 suggests it plays a role in metal ion homeostasis5. In humans, there are limited data to indicate that heterozygous loss-of-function N-terminal PrPC mutations may not be haploinsufficient, and hence, do not cause an explicit neurologic phenotype6 (see Truncating Mutations); whether homozygous loss of PrPC results in disease is not known2.

The PrPC protein is highly conserved from birds to mammals, indicating strong evolutionary protection, that demands importance in its biological function7. It was therefore, paradoxical to find that PRNP knockout mice displayed no overt phenotype, aside from a resistance to prion infection as concomitant expression of PrPC is required and rate-limiting5,8. Initial Prnp null mouse strains, the first designated Zurich I (ZrchI, PrnpZH1/ZH1) produced in a C57BL/6J x 129/Sv(ev) background9 and a second line of PrPC-deficient mice, known as Edinburgh (Edbg) produced with a pure 129/Ola genetic background10, developed and bred normally, albeit with subtle alterations in behaviour9. Their apparent normality seemed to exclude a physiological PrPC function that is essential for life2. If inactivation of a gene does not lead to an observed abnormal phenotype, there are three possibilities: (1) the abnormal phenotype is present under the conditions currently being used but is yet to be discovered, (2) the abnormal phenotype will only become evidence under environmental conditions that have not yet been tested, or (3) there is no abnormal phenotype11. Indeed, many subsequent studies have revealed that the Prnp knockout mouse has a myriad of phenotypes, some of which have been contested and many of which are subtle2,9,12 – see table.  Furthermore, PrP is one member of the prion protein family, that includes Doppel and Shadoo (see PrP Gene Structure), therefore, paralogous gene redundancy providing functional complementation11 and developmental plasticity12 may also mask the Prnp knockout mouse phenotype. PrPC-deficient mice from which the entire Prnp gene, and not only the open reading frame, was removed13-15 were found to develop progressive cerebellar ataxia, which was originally attributed to the loss of PrPC, but was later discovered to be due to the deletion of a splice acceptor site in exon 3 of Prnp16. This led to aberrant over-expression of the PrPC paralogous gene, Prnd, encoding Doppel16-18, causing selective neurodegeneration of cerebellar Purkinjie cells. Notably, the reintroduction of Prnp in mice over-expressing Prnd in the brain rescued the phenotype, suggesting a functional interaction between PrPC and Doppel in vivo19.

As seen in the table below, disparate functions have been attributed to PrPC on the basis of phenotypes seen in Prnp-deficient mice, yet none have been elucidated mechanistically, and while some studies were consistent among the different PrPC-deficient lines, others yielded contradictory results2,20. A genetic confounder has been shown to account for some of the observed phenotypes2,21. Replication of experiments in strictly co-isogenic mice (Zurich-3, Prnp-deficient mouse on a pure C57BL/6J genetic background)22 have revealed that some phenotypes, such as enhanced macrophage phagocytosis23, are due to polymorphic genes flanking Prnp22, including Sirpa20, which encodes the signal regulatory peptide-α, rather than loss of Prnp itself. Nevertheless, all Prnp-deficient mice are noted to develop a chronic demyelinating polyneuropathy22,24, and PrPC has been shown to promote myelin homeostasis by activating G protein-coupled receptor Gpr126 on Schwann cells25 thus, confirming the importance of PrPC in peripheral myelin maintenance21-22.

Table: Proposed physiological roles of PrPC. Studies of PrP knockout mice published to date are shown. Adapted from Wulf2 and Steele12. Bold indicates mixed genetic background of at least two distinct mouse strains. Italic indicates mice maintained on a single, pure genetic background
Proposed role of PrPC Phenotype of Prnp0/0 model system

Supportive report (mouse model / cell line)

Opposing report (mouse model / cell line)
Synaptic transmission and plasticity Reduced long-term potentiation Collinge J 1994 (ZH1) [26]
Manson JC 1995 (Edgb) [27]
Lledo PM 1996 (ZH1, ZH1 back-crossed to FVB) [28]
Laurén J 2009 (ZH1) [29]
  Reduced excitatory and inhibitory synaptic transmission Collinge J 1994 (ZH1) [26]
Carleton A 2001 (ZH1, Ngsk) [30]
Lledo PM 1996 (ZH1, ZH1 back-crossed to FVB) [28]
Herms JW 1995 (ZH1) [31]
Memory formation Reduced spatial learning and memory Criado JR 2005 (Edgb [back-]crossed to C57BL/10) [32] Büeler H 1992 (ZH1) [9]
  Reduced avoidance learning and memory Coitinho AS 2003 (ZH1) [33]
Nishida N 1997 (Ngsk) [34]
Lipp H-P 1998 (ZH1) [35]
Stabilisation of sleep and circadian rhythm  Altered circadian rhythm, increased sleep fragmentation, increased slow-wave activity after sleep deprivation Tobler I 1996 (ZH1, Edgb) [36] Sánchez-Alavez M 2007 (Edgb [back-]crossed to C57BL/10) [37]
Neuronal excitability  Reduced Kv4.2 currents Mercer RCC 2013 (ZH1, HEK293T) [38]  
  Reduced slow after hyperpolarisation and calcium-activated potassium currents Herms JW 2000 (ZH1) [39]
Fuhrmann M 2006 (ZH1) [40]
Collinge SB 1996 (ZH1) [41]
Mallucci GR 2002 (Tg35) [42]
Powell AD 2008 (ZH1) [43]
  Increased susceptibility to Kainate-induced seizures Carulla P 2011 (ZH1) [44] Striebel JF 2013 (Edbg [back-]crossed to C57BL/10) [45]
Calcium homeostasis Reduced VGCC currents Fuhrmann M 2006 (ZH1) [40] Powell AD 2008 (ZH1) [43]
  Increased calcium buffering Powell AD 2008 (ZH1) [43]  
Glutamate receptor function Increased NMDA currents, nociception and depressive-like behaviour Khosravani H 2008 (ZH1) [46]
Gadotti VM 2011 and 2012 (ZH1) [4748]
 
  Upregulation of Kainate receptor subunits Carulla P 2011 (ZH1) [44]  
Neurite outgrowth Delayed development of cerebellar circuitry Prestori F 2008 (ZH1) [49]  
  Reduced neurite outgrowth in vitro Beraldo FH 2011 (ZH1) [50]  
Toxicity elicited by oligomeric species Protected from reduction of long-term potentiation by toxic Amyloid-β species Laurén J 2009 (ZH1, Edbg backcrossed to C57BL6) [29] Balducci C 2010 (ZH1) [51]
Calella AM 2010 (ZH1) [52]
Kessels HW 2010 (Edgb [back-]crossed to C57BL/10) [53]
Cisse M 2011 (ZH1 backcrossed to FVB) [54]
Neuroprotection Larger lesions in model of acute cerebral ischaemia Weise J 2006 (ZH1) [55]
Doeppner TR 2015 (ZH1) [56]
Mitteregger G 2007 (ZH1) [57]
 
  Descreased SOD1 activity Brown DR 1997 (ZH1) [58] Waggoner DJ 2000 (ZH1) [59]
Copper, zinc, iron and lactate metabolism Reduced zinc content in primary neurons Watt NT 2012 (ZH1, SH-SY5Y) [60]  
  Increased lactate-uptake in cultured astrocytes Kleene R 2007 (ZH1) [61]  
  Altered iron and copper metabolism Gasperini L 2016 (ZH1 backcrossed to FVB) [62]  
Inflammatory response and phagocytosis Increased macrophage phagocytosis de Almeida 2005 (ZH1) [23] Nuvolone M 2013 (Edbg) [20]
Peripheral myelin maintenance    Bremer J 2010 (ZH1, Edgb) [24]
Nuvolone M 2016 (ZH3) [22]
Küffer A 2016 (ZH1 and ZH3) [25]
Henzi A 2020 (ZH3) [63]
 

References

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