The Retinoic Acid Receptor Beta (Rarb) Region of Mmu14 Is Associated with Prion Disease Incubation Time in Mouse

Abstract

In neurodegenerative conditions such as Alzheimer's and prion disease it has been shown that host genetic background can have a significant effect on susceptibility. Indeed, human genome-wide association studies (GWAS) have implicated several candidate genes. Understanding such genetic susceptibility is relevant to risks of developing variant CJD (vCJD) in populations exposed to bovine spongiform encephalopathy (BSE) and understanding mechanisms of neurodegeneration. In mice, aspects of prion disease susceptibility can be modelled by examining the incubation period following experimental inoculation. Quantitative trait linkage studies have already identified multiple candidate genes; however, it is also possible to take an individual candidate gene approach. Rarb and Stmn2 were selected as candidates based on the known association with vCJD. Because of the increasing overlap described between prion and Alzheimer's diseases we also chose Clu, Picalm and Cr1, which were identified as part of Alzheimer's disease GWAS. Clusterin (Clu) was considered to be of particular interest as it has already been implicated in prion disease. Approximately 1,000 heterogeneous stock (HS) mice were inoculated intra-cerebrally with Chandler/RML prions and incubation times were recorded. Candidate genes were evaluated by sequencing the whole transcript including exon-intron boundaries and potential promoters in the parental lines of the HS mice. Representative SNPs were genotyped in the HS mice. No SNPs were identified in Cr1 and no statistical association with incubation time was seen for Clu (P = 0.96) and Picalm (P = 0.91). Significant associations were seen for both Stmn2 (P = 0.04) and Rarb (P = 0.0005), however, this was only highly significant for Rarb. This data provides significant further support for a role for the Rarb region of Mmu14 and Stmn2 in prion disease.

Sod1 Deficiency Reduces Incubation Time in Mouse Models of Prion Disease

“…To look for an association between App , Il1-r1 , Sod1 and prion disease incubation time we used the Northport HS of mice as previously described [22], [23], [25], [33]. The stock was generated from eight parental lines (A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J and LP/J) and n = 1052 mice from generation 37 were inoculated with the Chandler/RML mouse adapted scrapie prion strain [22].…”

“…Other SNPs were chosen based on their ability to tag the SDP. Genotyping was carried out in approximately 400 mice representing the extremes of the incubation time distribution as this captures most of the power of the cross [25]. For details of primers and probes see Table S1.…”

“…In this study we carried out an association study for each of these genes in HS of mice. The mapping resolution available in the HS cross at generation 37 is approximately 1–2 cM which is too big to unambiguously ascribe an association to one gene although mapping to SDPs may help to narrow down the region [25].…”

“…To test whether App , Il1-r1 and Sod1 contribute to the naturally occurring variation in inbred lines of mice we used a heterogenous stock (HS) of mice inoculated with the Chandler/Rocky Mountain Laboratory (RML) mouse-adapted scrapie prion strain to look for a statistical association between prion disease incubation time and these genetic loci [22]–[25]. The Sod1 locus produced a highly significant association therefore we investigated this further by challenging Sod1 deficient mice ( Sod1 −/− ) with three different prion strains.…”

Genome wide association studies and prion disease

“…Much more significant is the finding that variants of the mouse synthetic region containing THRB-RARB are strongly associated with incubation time to RML prions in a study utilizing a heterogenous stock of mice. 38 The impact of RARB or THRB overexpression by transgenics or RARB or THRB knockout mice on incubation time to prion disease is awaited.…”