Cerebellar Oxidative DNA Damage and Altered DNA Methylation in the BTBR T+tf/J Mouse Model of Autism and Similarities with Human Post Mortem Cerebellum

Abstract

The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of OGG1 alterations in pathogenesis of autism.

The BTBR mouse model of idiopathic autism – Current view on mechanisms

“…Elevated levels of 8-oxo-7-hydrodeoxyguanosine, [8-oxodG] the most studied oxidative DNA lesion and an oxidative stress marker, and increased 5-methylcytosine [5mC] were associated with reduced expression of the 8-oxoguanine DNA-glycosylase 1 [ Ogg1 ]; and increased expression of de novo DNA methyltransferases 3a and 3b [ Dnmt3a and Dnmt3b ]. Similar changes were observed for human postmortem analysis of cerebellar epigenetic changes in ASD patients (Shpyleva et al, 2014). …”

“…Apart from the differential gene expression patterns, BTBR mice exhibit increased epigenetic alterations to the DNA in the cerebellum (Shpyleva et al 2014). Elevated levels of 8-oxo-7-hydrodeoxyguanosine, [8-oxodG] the most studied oxidative DNA lesion and an oxidative stress marker, and increased 5-methylcytosine [5mC] were associated with reduced expression of the 8-oxoguanine DNA-glycosylase 1 [ Ogg1 ]; and increased expression of de novo DNA methyltransferases 3a and 3b [ Dnmt3a and Dnmt3b ].…”

Seeking for potential pathogenic genes of major depressive disorder in the Gene Expression Omnibus database

“…The over‐expression of 8‐oxoguanine DNA glycosylase (OGG1) is the hallmark of the normal brain aging (Lu et al, ). It is reported that the interaction between OGG1 and X‐ray repair cross complementing 1 has been implicated in schizophrenia (Derakhshandeh, Saadat, Farrashbandi, & Saadat, ; Odemis et al, ; Psimadas et al, ; Saadat, Pakyari, & Farrashbandi, ) and autism spectrum disorder (Shpyleva et al, ; Xu, Rosales‐Reynoso, Barros‐Nunez, & Peprah, ; Young, McKinney, Ross, Wahle, & Boyle, ). It is found that the expression of OGG1 is increased in white matter oligodendrocytes of patients with MDD (Szebeni et al, ).…”

Oxidative stress and DNA damage in the mechanism of fetal alcohol spectrum disorders

“…It is important to note that an increase in oxidative stress, and 8‐oxoG in particular, has been implicated in many diseases, including autism (Shpyleva et al, ), Alzheimer's disease (Hofer & Perry, ; Isobe, Abe, & Terayama, ), Parkinson's disease (Kikuchi et al, ), epilepsy (Rumià et al, ), multiple system atrophy (MSA; Kikuchi et al, ), dementia with Lewy bodies (Lyras et al, ), and ALS; Chang et al, ) and FASD (Brocardo et al, ; Miller‐Pinsler et al, ; Patten et al, ). Interestingly, children with FASD demonstrate comorbidity with autism (Landgren, Svensson, Strömland, & Andersson Grönlund, ; Mukherjee, Layton, & Yacoub, ) and other phenotypes including abnormal peripheral nervous system disorder, conduct disorder, receptive language disorder, chronic serous otitis media, and expressive language disorder (Popova et al, ).…”