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

Peter A. Larsen, Michael W. Lutz, Kelsie E. Hunnicutt, Mirta Mihovilovic, Ann M. Saunders, Anne D. Yoder, Allen D. Roses

Research output: Contribution to journalShort surveypeer-review

27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)828-838
Number of pages11
JournalAlzheimer's and Dementia
Volume13
Issue number7
DOIs
StatePublished - Jul 2017
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank W.K. Gottschalk, S.S. Sundeth, O. Chiba-Falek, B.A. Sullivan, A.D. Brown, C.R. Campbell, R.J. Larsen, and L. Pinto for comments and discussion that helped to improve this manuscript. We are grateful for the support of Duke Research Computing and the Duke Data Commons (NIH 1S10OD018164-01). This is Duke Lemur Center publication number 1340.

Publisher Copyright:
© 2017 The Authors

Keywords

  • A-to-I editing
  • Alternative splicing
  • Alzheimer's disease
  • Epigenetics
  • H3K9
  • Inflammation
  • LINE
  • Neuroepigenetics
  • Nonsense-mediated decay
  • Parkinson's disease
  • Retrotransposon
  • SINE
  • Somatic mosaicism
  • Somatic mutation
  • Spliceosome

Fingerprint

Dive into the research topics of 'The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease'. Together they form a unique fingerprint.

Cite this