Prion Protein Polymorphisms Affect Chronic Wasting Disease Progression

Analysis of the PRNP gene in cervids naturally infected with chronic wasting disease (CWD) suggested that PRNP polymorphisms affect the susceptibility of deer to infection. To test this effect, we orally inoculated 12 white-tailed deer with CWD agent. Three different PRNP alleles, wild-type (wt; glutamine at amino acid 95 and glycine at 96), Q95H (glutamine to histidine at amino acid position 95) and G96S (glycine to serine at position 96) were represented in the study cohort with 5 wt/wt, 3 wt/G96S, and 1 each wt/Q95H and Q95H/G96S. Two animals were lost to follow-up due to intercurrent disease. The inoculum was prepared from Wisconsin hunter-harvested homozygous wt/wt animals. All infected deer presented with clinical signs of CWD; the orally infected wt/wt had an average survival period of 693 days post inoculation (dpi) and G96S/wt deer had an average survival period of 956 dpi. The Q95H/wt and Q95H/G96S deer succumbed to CWD at 1,508 and 1,596 dpi respectively. These data show that polymorphisms in the PRNP gene affect CWD incubation period. Deer heterozygous for the PRNP alleles had extended incubation periods with the Q95H allele having the greatest effect

Incubation period and duration of clinical period.

<p>Internal red bars indicate clinical disease. Day zero is the day the oral inoculations were initiated.</p

Survival curve of white-tailed deer orally challenged with CWD agents.

<p>Animals with only wild type alleles (blue) succumb to disease faster than individuals carrying at least one of the polymorphisms in positions 95 and 96 (Red). Wt/Q95H and Q95H/G96S animals present longer incubation periods and succumb to disease at similar times.</p

PrP^CWD electrophoretic patterns in different <i>PRNP</i> backgrounds.

<p>Brain homogenates with (+) or without (−) PK digestion were resolved by western blot using monoclonal antibody 8G8.</p

Immunohistochemical detection of PrP^CWD in the obex region of white tailed deer infected with CWD: A) wt/wt, B) wt/G96S, C) wt/Q95H and D) Q95H/G96S.

<p>Regions are indicated as: V = dorsal nucleus of the vagal nerve; S = nucleus of the solitary tract; T = spinal trigeminal nucleus and H = hypoglossal nucleus.</p

<i>PRNP</i> locus traits of orally challenged white-tailed deer.

<p>Silent polymorphisms, the presence or absence of the pseudo-gene and amino acid substitutions linked to disease progression (highlighted) are listed for each animal. Only one animal presented both amino acid substitutions in different alleles at the same time (Bold font).</p