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

doi:10.1016/j.jalz.2017.01.017

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 journal › Short survey › peer-review

51 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 language	English (US)
Pages (from-to)	828-838
Number of pages	11
Journal	Alzheimer's and Dementia
Volume	13
Issue number	7
DOIs	https://doi.org/10.1016/j.jalz.2017.01.017
State	Published - Jul 2017
Externally published	Yes

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

Publisher link

10.1016/j.jalz.2017.01.017

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Cite this

Larsen, P. A., Lutz, M. W., Hunnicutt, K. E., Mihovilovic, M., Saunders, A. M., Yoder, A. D., & Roses, A. D. (2017). The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease. Alzheimer's and Dementia, 13(7), 828-838. https://doi.org/10.1016/j.jalz.2017.01.017

The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease. / Larsen, Peter A.; Lutz, Michael W.; Hunnicutt, Kelsie E. et al.
In: Alzheimer's and Dementia, Vol. 13, No. 7, 07.2017, p. 828-838.

Research output: Contribution to journal › Short survey › peer-review

Larsen, PA, Lutz, MW, Hunnicutt, KE, Mihovilovic, M, Saunders, AM, Yoder, AD & Roses, AD 2017, 'The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease', Alzheimer's and Dementia, vol. 13, no. 7, pp. 828-838. https://doi.org/10.1016/j.jalz.2017.01.017

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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.",

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AU - Mihovilovic, Mirta

AU - Saunders, Ann M.

AU - Yoder, Anne D.

AU - Roses, Allen D.

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