Abstract
Nearly half of the coding genes in the human genome were found to belong to transposable elements (TEs). First discovered in the late 1940s, they often encode multifunctional proteins and intricate noncoding regulatory sequences, aiding their propagation. TEs include the long-terminal repeat (LTR) retrotransposons, which in turn encompass endogenous retroviruses (ERVs). Human ERVs (HERVs) represent 8% of the coding genome and were integrated into the human genome through a process called endogenization. HERVs are categorized into several classes, each undergoing distinct endogenization events and containing various subclasses. Previously considered "junk DNA," HERVs are now recognized as active elements that play roles in genetic regulation, immune response modulation, and the development of host species by expressing functional proteins. Nevertheless, abnormal HERV expression is linked to several neurodevelopmental (NDDs) and neuropsychiatric disorders (NPDs) with chronic inflammatory background, including schizophrenia, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). Notably, dysregulation of HERVs in these disorders may not only be a consequence of the disease process, but rather play an active role in their pathogenesis.
Establishing causal relationships between altered HERV expression and brain disorders in humans is challenging, if not impossible, due to technical and ethical reasons. Therefore, the complementary use of animal models is expected to significantly advance our understanding of how increased HERV expression alters brain functions in a translational manner that is relevant to NDDs and NPDs. Indeed, they offer the unique opportunity to identify specific cellular and molecular mechanism underlying the emergence of disease-relevant behavioural and cognitive dysfunctions. Furthermore, animal models are suitable experimental tools to explore environmental factors that trigger the activation of retroviral elements. Finally, animal models allow offer an important preclinical platform for assessing the efficacy and mechanistic aspects of novel interventions against brain disorders associated with abnormal expression of HERVs.
Against this background, the doctoral work contained in this thesis aimed to investigate the relationships between altered ERV expression and emergence of brain and behavioural dysfunctions, with particular focus on NDDs and NPDs.
The first specific objective was to conduct a comprehensive literature research, focusing on the bi-directional relationship between HERV expression and inflammation. This literature search revealed that there is a critical gap in the current understanding of HERVs in relation to inflammation, and vice versa. It is highlighted that there are numerous entry points to the reciprocal relationship between inflammation and HERV expression, including initial infections with HERV-activating pathogens, exposure to non-infectious inflammatory stimuli, and conditions in which epigenetic silencing of ERV elements is disrupted.
The second specific objective was to assess the effects of maternal immune activation (MIA), a transdiagnostic risk factor for NDDs and NPDs, on expression of murine ERVs in a mouse model of viral-like MIA. Combining molecular and behavioural analyses in mice, this work provided a proof of concept that an inflammatory stimulus, even when initiated in prenatal life, has the potential of altering ERV expression across foetal to adult stages of development. Moreover, the findings from this work highlighted that risk and resilience to MIA are associated with differential ERV expression, suggesting that early-life exposure to inflammatory factors may play a role in determining disease susceptibility by inducing persistent alterations in the expression of endogenous retroviral elements.
The third and fourth specific objectives were to investigate causal mechanisms between HERV-W expression and brain dysfunctions relevant to NDDs and NPDs, and to test therapeutic treatments against HERV-W-associated brain dysfunctions. These objectives were achieved through experimental work using a mouse model that recapitulates the expression of the human-specific HERV-W Envelope (ENV) protein. This transgenic mouse line is currently the only existing mouse model of human-specific HERV-W ENV expression and allowed insights into neurobiological disease pathways affected by HERV-W ENV expression. Combining behavioural and molecular analyses with pharmacological interventions, the findings from this work suggest HERV-W ENV has the capacity to disrupt various behavioural and cognitive functions and to alter the brain transcriptome in a manner that is highly relevant to NDDs and NPDs. Moreover, this work identified epigenetic pathways that offered avenues for pharmacological interventions against behavioural and cognitive deficits induced by increased HERW-W ENV expression.
Taken together, the doctoral work contained in this thesis corroborates the aetiopathological role of HERVs in NDDs and NPDs and provides novel preclinical evidence suggesting that abnormal expression of these endogenous retroviral elements are causally related to the emergence of specific dysfunctions in brain and behaviour. Moreover, the work presented in this thesis identifies novel pharmacological approaches against behavioural and cognitive dysfunctions induced by HERV-W ENV expression, indicating that the pathological effects of HERV-W ENV expression are amenable to therapeutic interventions.
Herrero, Felisa