Warning SINEs: Alu elements, evolution of the human brain, and the spectrum of neurological disease

Abstract

AbstractAlu 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.List of AbbreviationsA-to-Iadenosine-to-inosineADAlzheimer’s DiseaseADARadenosine deaminase acting on RNAALSAmyotrophic Lateral SclerosisAMPAα-amino-3-hydroxy-5methyl-4-isoxazole propionateAPPamyloid precursor proteincircRNAscircular RNAsCNScentral nervous systemFLAMfree left Alu monomerLINElong interspersed elementL1long interspersed element-1LTRlong-terminal repeatmRNAmessenger RNAPDParkinson’s Diseasepre-mRNAprecursor messenger RNASEDssuper-enhancer domainsSINEshort-interspersed elementTADstopologically associating domainsTOMMtranslocase of outer mitochondrial membrane