Abstract
Alu elements are a highly successful family of primate-specific retrotransposons that have fundamentally shaped primate evolution, including the evolution of our own species. Alus play critical roles in the formation of neurological networks and the epigenetic regulation of biochemical processes throughout the central nervous system (CNS), and thus are hypothesized to have contributed to the origin of human cognition. Despite the benefits that Alus provide, deleterious Alu activity is associated with a number of neurological and neurodegenerative disorders. In particular, neurological networks are potentially vulnerable to the epigenetic dysregulation of Alu elements operating across the suite of nuclear-encoded mitochondrial genes that are critical for both mitochondrial and CNS function. Here, we highlight the beneficial neurological aspects of Alu elements as well as their potential to cause disease by disrupting key cellular processes across the CNS. We identify at least 37 neurological and neurodegenerative disorders wherein deleterious Alu activity has been implicated as a contributing factor for the manifestation of disease, and for many of these disorders, this activity is operating on genes that are essential for proper mitochondrial function. We conclude that the epigenetic dysregulation of Alu elements can ultimately disrupt mitochondrial homeostasis within the CNS. This mechanism is a plausible source for the incipient neuronal stress that is consistently observed across a spectrum of sporadic neurological and neurodegenerative disorders.
Highlights
Retrotransposons are mobile genetic elements that utilize an RNA intermediate to copy and paste themselves throughout the genome
We identify at least 37 neurological and neurodegenerative disorders wherein deleterious Alu activity has been implicated as a contributing factor for the manifestation of disease, and for many of these disorders, this activity is operating on genes that are essential for proper mitochondrial function
Many lines of evidence connect Alu elements with neurogenesis and critical neuronal biochemical processes, including somatic retrotransposition in developing neurons, formation of regulatory circRNAs that are enriched in the central nervous system (CNS) and concentrated at synapses (Jeck et al 2013; Rybak-Wolf et al 2015; Chen and Schuman 2016; Floris et al 2017), regulation of genes that are essential for proper neuron function (e.g., ACE, SMN1, SMN2, SLC6A4; Wu et al 2013; Ottesen et al 2017; Schneider et al 2017), and elevated adenosine-toinosine (A-to-I) RNA editing in the brain (Mehler and Mattick 2007; Kurnosov et al 2015; Behm and Öhman 2016)
Summary
Retrotransposons are mobile genetic elements that utilize an RNA intermediate to copy and paste themselves throughout the genome. Many lines of evidence connect Alu elements with neurogenesis and critical neuronal biochemical processes, including somatic retrotransposition in developing neurons (in parallel to L1 retrotransposition; Baillie et al 2011; Kurnosov et al 2015), formation of regulatory circRNAs that are enriched in the central nervous system (CNS) and concentrated at synapses (Jeck et al 2013; Rybak-Wolf et al 2015; Chen and Schuman 2016; Floris et al 2017), regulation of genes that are essential for proper neuron function (e.g., ACE, SMN1, SMN2, SLC6A4; Wu et al 2013; Ottesen et al 2017; Schneider et al 2017), and elevated adenosine-toinosine (A-to-I) RNA editing in the brain (Mehler and Mattick 2007; Kurnosov et al 2015; Behm and Öhman 2016).
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