title: Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age.
abstract: Expansion of CAG/CTG trinucleotide repeats causes numerous inherited neurological disorders, including Huntington's disease (HD), several spinocerebellar ataxias and myotonic dystrophy type 1. Expanded repeats are genetically unstable with a propensity to further expand when transmitted from parents to offspring. For many alleles with expanded repeats, extensive somatic mosaicism has been documented. For CAG repeat diseases, dramatic instability has been documented in the striatum, with larger expansions noted with advancing age. In contrast, only modest instability occurs in the cerebellum. Using microarray expression analysis, we sought to identify the genetic basis of these regional instability differences by comparing gene expression in the striatum and cerebellum of aged wild-type C57BL/6J mice. We identified eight candidate genes enriched in cerebellum, and validated four--Pcna, Rpa1, Msh6 and Fen1--along with a highly associated interactor, Lig1. We also explored whether expression levels of mismatch repair (MMR) proteins are altered in a line of HD transgenic mice, R6/2, that is known to show pronounced regional repeat instability. Compared with wild-type littermates, MMR expression levels were not significantly altered in R6/2 mice regardless of age. Interestingly, expression levels of these candidates were significantly increased in the cerebellum of control and HD human samples in comparison to striatum. Together, our data suggest that elevated expression levels of DNA replication and repair proteins in cerebellum may act as a safeguard against repeat instability, and may account for the dramatically reduced somatic instability present in this brain region, compared with the marked instability observed in the striatum.
authors.affiliation: Department of Pediatrics.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Mason
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tomé
authors.forename: Jodie P
authors.initials: JP
authors.lastname: Simard
authors.forename: Randell T
authors.initials: RT
authors.lastname: Libby
authors.forename: Theodor K
authors.initials: TK
authors.lastname: Bammler
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Morton
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pearson
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000367:Age Factors; D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D045585:Flap Endonucleases / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053842:Microsatellite Instability; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D051716:Replication Protein A / Q000235:genetics; D018911:Trinucleotide Repeats
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C000607892:LIG1 protein, human; C000607894:Lig1 protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D051716:Replication Protein A; C497168:Rpa1 protein, mouse; C572473:Fen1 protein, mouse; D045585:Flap Endonucleases; D011088:DNA Ligases; D000072481:DNA Ligase ATP