Larsen Peter A, Lutz Michael W, Hunnicutt Kelsie E, Mihovilovic Mirta, Saunders Ann M, Yoder Anne D, Roses Allen D
Department of Biology, Duke University, Durham, NC, USA.
Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
Alzheimers Dement. 2017 Jul;13(7):828-838. doi: 10.1016/j.jalz.2017.01.017. Epub 2017 Feb 24.
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.
据推测，逆转录转座子在灵长类动物进化中发挥了重要作用，而人类中增强的神经逆转录转座子活性可能是更高认知功能起源的基础。作为这种增强活性的潜在后果，神经元很可能易受有害的逆转录转座子途径影响，这些途径会破坏线粒体功能。在编码对线粒体前体蛋白转运至关重要的β-桶状蛋白的TOMM40基因中就观察到了一个例子。灵长类动物特有的Alu逆转录转座子多次插入TOMM40内含子，并且至少有一种与迟发性阿尔茨海默病相关的变体起源于一次Alu插入事件。我们提供了线粒体基因中Alu含量丰富的证据，并推测Alu可破坏神经元中的线粒体群体，从而为进行性神经功能障碍奠定基础。这种Alu神经变性假说与数十年的研究结果相符，并为神经元线粒体稳态的破坏提供了一种合理的机制，最终演变成神经退行性疾病。
