Human Endogenous Retroviruses as Pathogenic Factors in the Development of Schizophrenia

Abstract

Schizophrenia is a complex disorder, characterized by the interplay between genetic and environmental factors. Human endogenous retroviruses (HERVs), genetic elements that originated from infections by exogenous retroviruses millions of years ago, comprise ~8% of the human genome. Here, we provide a comprehensive review of accumulating evidence, detailing HERV aberrancies associated with schizophrenia. Studies examining the genome, transcriptome, and proteome of individuals with schizophrenia provide data that support the association of these viral elements with the disorder. Molecular differences can be found within the central nervous system and peripheral tissues. However, additional studies are needed to substantiate the reported link and to address several discrepancies among previous investigations. We further discuss potentially relevant pathogenic mechanisms to the development of schizophrenia.

Do Human Endogenous Retroviruses Contribute to Multiple Sclerosis, and if So, How?

“…Enhanced levels of MSRV have been reported by researchers examining MS plaques post-mortem [ 45 , 46 , 62 ] and the presence of MSRV virions in the blood and cerebrospinal fluid (CSF) of MS patients has been reported by several groups [ 43 , 61 , 63 – 66 ]. The presence of MSRV has also been reported in patients with other neurological conditions, albeit at lower frequencies [ 21 , 63 , 65 , 67 ], and in a small minority of disease-free volunteers [ 44 , 63 ]. Dolei and fellow workers reported the presence of MRSV in the plasma in 100% of a patient cohort with active MS [ 63 ].…”

“…However, while the retention of HERV sequences in the human genome is likely because the beneficial effects on the species outweigh any detrimental effects in individuals [ 5 , 16 , 17 ], the danger of inappropriate HERV expression to individuals may be considerable. For example, HERV expression can initiate and increase the activation of immune and inflammatory pathways [ 16 , 18 – 20 ] and dysregulate gene pathways by affecting the levels of DNA transcription factors such as cAMP (cyclic adenosine monophosphate) response element-binding protein (CREB) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [ 21 , 22 ]. Abnormal HERV expression can also potentially compromise neurotransmission and brain chemistry [ 23 , 24 ].…”

How and why do T cells and their derived cytokines affect the injured and healthy brain?

“…The consequence is aberrant expression of nearby genes (and non-coding RNAs) on the chromosome and behavioural hyperactivity. In humans, increased levels of ERV mRNA have been associated with ageing and psychiatric disorders such as schizophrenia and bipolar disorder 94–97 . Even when silenced, the presumably benign ERV sequences can influence the transcription of nearby genes through several mechanisms — for example, by providing promoters for protein-encoding genes or by facilitating the production of microRNAs, long non-coding RNAs and antisense RNAs 98–100 .…”

Peroxisome Proliferator Activated Receptor Agonists Modulate Transposable Element Expression in Brain and Liver

“…Transposable elements have been implicated in many pathological conditions, including approximately 100 single-gene diseases ( Hancks and Kazazian, 2012 ), such as hemophilia A ( Sukarova et al, 2001 ; Ganguly et al, 2003 ; Green et al, 2008 ), and cystic fibrosis ( Chen et al, 2008 ). Retrotransposons (ERVs and LINE1 elements) have also been linked to more complex diseases including diabetes ( Pascual et al, 2001 ; Dickerson et al, 2008 ), cancers [for review, see ( Burns, 2017 )], and several psychiatric disorders ( Guffanti et al, 2014 ), such as alcohol and cocaine addiction ( Maze et al, 2011 ; Ponomarev et al, 2012 ), autism ( Balestrieri et al, 2012 ), Attention Deficit Hyperactivity Disorder ( Balestrieri et al, 2014 ), depression ( Weis et al, 2007 ), schizophrenia ( Yolken et al, 2000 ; Karlsson et al, 2001 , 2004 ; Frank et al, 2005 ; Weis et al, 2007 ; Dickerson et al, 2008 ; Perron et al, 2008 , 2012a , b ; Yao et al, 2008 ; Huang et al, 2011 ; Lin et al, 2011 ; Bundo et al, 2014 ; Slokar and Hasler, 2015 ), bipolar disorder ( Yolken et al, 2000 ; Weis et al, 2007 ; Frank et al, 2005 ; Perron et al, 2012b ), post-traumatic stress disorder ( Ponomarev et al, 2010 ; Rusiecki et al, 2012 ), Rett syndrome ( Muotri et al, 2010 ), and neurodegeneration ( Cartault et al, 2012 ; Li et al, 2012 ). Besides their clinical uses for dyslipidemia and diabetes, PPAR agonists have shown therapeutic potential (mostly preclinical evidence) for several brain diseases including neurodegeneration ( Bordet et al, 2006 ; Barbiero et al, 2014 ; Fidaleo et al, 2014 ; Avagliano et al, 2016 ; Dickey et al, 2016 ; Makela et al, 2016 ; Zhou et al, 2016 ; Wang Y. et al, 2017 ), mood disorders ( Kemp et al, 2014 ; Ji et al, 2015 ; Scheggi et al, 2016 ;…”