The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease.
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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.
Published Version (Please cite this version)10.1016/j.jalz.2017.01.017
Publication InfoLarsen, Peter A; Lutz, Michael W; Hunnicutt, Kelsie E; Mihovilovic, Mirta; Saunders, Ann M; Yoder, Anne D; & Roses, Allen D (2017). The Alu neurodegeneration hypothesis: A primate-specific mechanism for neuronal transcription noise, mitochondrial dysfunction, and manifestation of neurodegenerative disease. Alzheimers Dement. 10.1016/j.jalz.2017.01.017. Retrieved from https://hdl.handle.net/10161/13815.
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Associate Professor in Neurology
Developing and using computational biology methods to understand the genetic basis of disease with a focus on Alzheimer’s Disease. Recent work has focused on identification and validation of clinically-relevant biomarkers for Alzheimer’s disease and Alzheimer’s disease with Lewy bodies.
Jefferson-Pilot Corporation Professor of Neurobiology, in the School of Medicine
Allen D. Roses has established an international reputation for his work in pharmacogenetics, exploratory drug discovery, and clinical neuroscience. Dr. Roses founded Cabernet Pharmaceuticals in 2008 to provide pharmacogenetics (PGx) and project-management services to pharmaceutical and biotechnology companies, clinical-research and managed-healthcare organizations, and academic institutions. He has formed a team of consultants with deep experience in the practical application of
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Adjunct Associate Professor in the Department of Neurology
The primary focus of the laboratory is the molecular genetics of Alzheimer's disease (AD), with particular emphasis on the identification and characterization of genetic susceptibility genes for late-onset AD. Since our initial discovery in 1993 of a strong genetic risk factor for AD, we have done extensive work in defining the association in familial and sporadic AD, most recently for use as a diagnostic adjunct in the clinic. We are also actively testing candidate genes for chromosome 1
Braxton Craven Distinguished Professor of Evolutionary Biology
My work integrates field inventory activities with molecular phylogenetic techniques and geospatial analysis to investigate Madagascar, an area of the world that is biologically complex, poorly understood, and urgently threatened. Madagascar has been designated as one of the most critical geographic priorities for conservation action, retaining less than 10% of the natural habitats that existed before human colonization. It is critical that information be obtained as quickly as possible to docum
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