TY - JOUR
T1 - Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington's disease
AU - Tang, Bin
AU - Seredenina, Tamara
AU - Coppola, Giovanni
AU - Kuhn, Alexandre
AU - Geschwind, Daniel H.
AU - Luthi-Carter, Ruth
AU - Thomas, Elizabeth A.
N1 - Funding Information:
Thanks to Keith Harshman at the Lausanne DNA Array Facility for facilitating the processing of the R6/2-Q150 CAG microarray samples. These studies were funded, in part, by NIH grant NS44169 to E.A.T.
PY - 2011/6
Y1 - 2011/6
N2 - R6/2 transgenic mice with expanded CAG repeats (>300) have a surprisingly prolonged disease progression and longer lifespan than prototypical parent R6/2 mice (carrying 150 CAGs); however, the mechanism of this phenotype amelioration is unknown. We compared gene expression profiles in the striatum of R6/2 transgenic mice carrying ~300 CAG repeats (R6/2Q300 transgenic mice) to those carrying ~150 CAG repeats (R6/2Q150 transgenic mice) and littermate wildtype controls in order to identify genes that may play determinant roles in the time course of phenotypic expression in these mice. Of the top genes showing concordant expression changes in the striatum of both R6/2 lines, 85% were decreased in expression, while discordant expression changes were observed mostly for genes upregulated in R6/2Q300 transgenic mice. Upregulated genes in the R6/2Q300 mice were associated with the ubiquitin ligase complex, cell adhesion, protein folding, and establishment of protein localization. We qPCR-validated increases in expression of genes related to the latter category, including Lrsam1, Erp29, Nasp, Tap1, Rab9b, and Pfdn5 in R6/2Q300 mice, changes that were not observed in R6/2 mice with shorter CAG repeats, even in late stages (i.e., 12weeks of age). We further tested Lrsam1 and Erp29, the two genes showing the greatest upregulation in R6/2Q300 transgenic mice, for potential neuroprotective effects in primary striatal cultures overexpressing a mutated human huntingtin (htt) fragment. Overexpression of Lrsam1 prevented the loss of NeuN-positive cell bodies in htt171-82Q cultures, concomitant with a reduction of nuclear htt aggregates. Erp29 showed no significant effects in this model. This is consistent with the distinct pattern of htt inclusion localization observed in R6/2Q300 transgenic mice, in which smaller cytoplasmic inclusions represent the major form of insoluble htt in the cell, as opposed to large nuclear inclusions observed in R6/2Q150 transgenic mice. We suggest that the prolonged onset and disease course observed in R6/2 mice with greatly expanded CAG repeats might result from differential upregulation of genes related to protein localization and clearance. Such genes may represent novel therapeutic avenues to decrease htt aggregate toxicity and cell death in HD patients, with Lrsam1 being a promising, novel candidate disease modifier.
AB - R6/2 transgenic mice with expanded CAG repeats (>300) have a surprisingly prolonged disease progression and longer lifespan than prototypical parent R6/2 mice (carrying 150 CAGs); however, the mechanism of this phenotype amelioration is unknown. We compared gene expression profiles in the striatum of R6/2 transgenic mice carrying ~300 CAG repeats (R6/2Q300 transgenic mice) to those carrying ~150 CAG repeats (R6/2Q150 transgenic mice) and littermate wildtype controls in order to identify genes that may play determinant roles in the time course of phenotypic expression in these mice. Of the top genes showing concordant expression changes in the striatum of both R6/2 lines, 85% were decreased in expression, while discordant expression changes were observed mostly for genes upregulated in R6/2Q300 transgenic mice. Upregulated genes in the R6/2Q300 mice were associated with the ubiquitin ligase complex, cell adhesion, protein folding, and establishment of protein localization. We qPCR-validated increases in expression of genes related to the latter category, including Lrsam1, Erp29, Nasp, Tap1, Rab9b, and Pfdn5 in R6/2Q300 mice, changes that were not observed in R6/2 mice with shorter CAG repeats, even in late stages (i.e., 12weeks of age). We further tested Lrsam1 and Erp29, the two genes showing the greatest upregulation in R6/2Q300 transgenic mice, for potential neuroprotective effects in primary striatal cultures overexpressing a mutated human huntingtin (htt) fragment. Overexpression of Lrsam1 prevented the loss of NeuN-positive cell bodies in htt171-82Q cultures, concomitant with a reduction of nuclear htt aggregates. Erp29 showed no significant effects in this model. This is consistent with the distinct pattern of htt inclusion localization observed in R6/2Q300 transgenic mice, in which smaller cytoplasmic inclusions represent the major form of insoluble htt in the cell, as opposed to large nuclear inclusions observed in R6/2Q150 transgenic mice. We suggest that the prolonged onset and disease course observed in R6/2 mice with greatly expanded CAG repeats might result from differential upregulation of genes related to protein localization and clearance. Such genes may represent novel therapeutic avenues to decrease htt aggregate toxicity and cell death in HD patients, with Lrsam1 being a promising, novel candidate disease modifier.
KW - Gene expression
KW - Huntington's disease
KW - Inclusion
KW - Neuroprotection
KW - Striatum
UR - http://www.scopus.com/inward/record.url?scp=79954630190&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2011.02.008
DO - 10.1016/j.nbd.2011.02.008
M3 - Article
C2 - 21334439
AN - SCOPUS:79954630190
SN - 0969-9961
VL - 42
SP - 459
EP - 467
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -