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

• Published in: Chromosome research Vol. 26; no. 1-2; pp. 93 - 111
• Main Authors: Larsen, Peter A., Hunnicutt, Kelsie E., Larsen, Roxanne J., Yoder, Anne D., Saunders, Ann M.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.03.2018; Springer Nature B.V
• Subjects: Alu elements; Alu Elements - physiology; Animal Genetics and Genomics; biochemical pathways; Biological Evolution; Biomedical and Life Sciences; brain; Brain - physiology; Cell Biology; Central nervous system; Chemical elements; Cognition; Disease; Epigenetics; Evolution; Genome, Human; Homeostasis; Human Genetics; Humans; Life Sciences; Mitochondria; Mitochondrial DNA; mitochondrial genes; Nervous System Diseases - genetics; Neurodegenerative diseases; Neurogenesis; Neurological diseases; Neurological disorders; neurons; Original; Original Article; Parkinson's disease; Plant Genetics and Genomics; Retroelements; retrotransposons; Spectrum analysis; Brain connectome; A-to-I editing; Mitochondria; Alzheimer’s disease; Epigenetics; Mosaic brain; Parkinson’s disease
• ISSN: 0967-3849; 1573-6849; 1573-6849
• DOI: 10.1007/s10577-018-9573-4

Alu elements are a highly successful family of primate-specific retrotransposons that have fundamentally shaped primate evolution, including the evolution of our own species. Alu s 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.