The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease.

Journal Article

It is hypothesized that retrotransposons have played a fundamental role in primate evolution and that enhanced neurologic retrotransposon activity in humans may underlie the origin of higher cognitive function. As a potential consequence of this enhanced activity, it is likely that neurons are susceptible to deleterious retrotransposon pathways that can disrupt mitochondrial function. An example is observed in the TOMM40 gene, encoding a β-barrel protein critical for mitochondrial preprotein transport. Primate-specific Alu retrotransposons have repeatedly inserted into TOMM40 introns, and at least one variant associated with late-onset Alzheimer's disease originated from an Alu insertion event. We provide evidence of enriched Alu content in mitochondrial genes and postulate that Alus can disrupt mitochondrial populations in neurons, thereby setting the stage for progressive neurologic dysfunction. This Alu neurodegeneration hypothesis is compatible with decades of research and offers a plausible mechanism for the disruption of neuronal mitochondrial homeostasis, ultimately cascading into neurodegenerative disease.

Full Text

Duke Authors

Cited Authors

  • Larsen, PA; Lutz, MW; Hunnicutt, KE; Mihovilovic, M; Saunders, AM; Yoder, AD; Roses, AD

Published Date

  • July 2017

Published In

Volume / Issue

  • 13 / 7

Start / End Page

  • 828 - 838

PubMed ID

  • 28242298

Electronic International Standard Serial Number (EISSN)

  • 1552-5279

International Standard Serial Number (ISSN)

  • 1552-5260

Digital Object Identifier (DOI)

  • 10.1016/j.jalz.2017.01.017

Language

  • eng