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

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.

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

“…298 is mitochondrial dysfunction (Lin and Beal 2006; Rugarli and Langer 2012; Gottschalk et al 2992014;Petschner et al 2017). However, we have previously shown that mitonuclear genes are 300 enriched with Alu elements when compared to random(Larsen et al 2017), which is 301 consistent with earlier observations regarding the non-random insertion of Alu elements into 302 genes associated with transcriptionally active regions of the genome(Grover et al 2003; de 303 Andrade et al 2011). Thus, it is likely that Alu-mediated gene regulatory processes are 304 actively influencing mitonuclear gene expression, regulation, and protein function through 305 the pathways discussed above and reviewed in(Chen and Yang 2017).…”

“…Thus, it is likely that Alu-mediated gene regulatory processes are 304 actively influencing mitonuclear gene expression, regulation, and protein function through 305 the pathways discussed above and reviewed in(Chen and Yang 2017). Knowing this, the 306 dysregulation of epigenetic Alu regulatory pathways is a plausible source for mitochondrial 307 stress and dysfunction, with the CNS being particularly vulnerable(Larsen et al 2017). Such 308 a mechanism could contribute to the initial activation of complex mitochondrial stress 309 pathways and incipient neuronal stress associated with sporadic neurologic disorders (e.g., 310inflammation, immune response, mitophagy, etc.).…”

Tropical heterothermy is “cool”: The expression of daily torpor and hibernation in primates

“…A number of aged mouse lemurs do show Alzheimer's‐like symptoms, such as brain atrophy, amyloid plaques, and neurofibrillary tangles. Thus, mouse lemurs are the best available primate model to understand brain aging and disease . Although relatively little work has been produced, there is indication that dwarf lemurs also show reversible phosphorylation between cycles of hibernation, which can prove highly relevant to the field of brain degenerative conditions …”

“…Thus, mouse lemurs are the best available primate model to understand brain aging and disease. 95,97,98 Although relatively little work has been produced, there is indication that dwarf lemurs also show reversible phosphorylation between cycles of hibernation, which can prove highly relevant to the field of brain degenerative conditions. 99 Another biomedical approach related to neurodegenerative diseases is examining the role of melatonin as effective protection against oxidative stress and using it as co-treatment of Parkinson's and other neurodegenerative conditions.…”

Letter

“…Also, the difficulty in developing novel interventions to detect [1–57], delay [58–69], or halt disease progression continues to be an important hurdle. The well‐recognized public health and economic imperative [70–83] posed by the disease continues to be an important motivator to communicate new knowledge across multiple disciplines that will help increase the likelihood of unlocking the complexity of neurodegeneration [84–90] associated with many dementing illnesses.…”