Frontotemporal dementia (FTD) is the second most prevalent form of pre-senile dementia after Alzheimer’s disease. Amyotrophic lateral sclerosis (ALS) can overlap genetically, pathologically and clinically with FTD indicating the two conditions are ends of a spectrum and may share common pathological mechanisms. FTD-ALS causing mutations are known to be involved in endosomal trafficking and RNA regulation. Using an unbiased genome-wide genetic screen to identify mutations affecting an FTD-ALS related phenotype in Drosophila caused by CHMP2B^Intron5 expression, we have uncovered repressors of retrovirus (RV) activity as modifiers of CHMP2B^Intron5 toxicity. We report that neuronal expression of CHMP2B^Intron5 causes an increase in the activity of the endogenous Drosophila RV, gypsy, in the nervous system. Genetically blocking Drosophila gypsy activation and pharmacologically inhibiting viral reverse transcriptase activity prevents degenerative phenotypes observed in fly and rat neurons. These findings directly link endosomal dysfunction to RV derepression in an FTD-ALS model without TDP-43 pathology. These observations may contribute an understanding to previous discoveries of RV activation in ALS affected patients.

中文翻译：

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额颞叶痴呆 CHMP2BIntron5 模型中的逆转录病毒再激活。

额颞叶痴呆 (FTD) 是继阿尔茨海默病之后第二常见的老年痴呆症。肌萎缩侧索硬化症 (ALS) 在遗传、病理和临床上与 FTD 重叠，表明这两种情况是一个谱系的末端，并且可能具有共同的病理机制。已知引起突变的 FTD-ALS 与内体运输和 RNA 调节有关。使用无偏见的全基因组遗传筛选来识别影响由 CHMP2B Intron5 表达引起的^果蝇FTD -ALS 相关表型的突变，我们发现了作为CHMP2B Intron5^毒性修饰剂的逆转录病毒 (RV) 活性抑制因子。我们报告 CHMP2B Intron5 的神经元^表达导致神经系统中内源性果蝇RV，吉普赛人的活性增加。基因阻断果蝇吉普赛活化和药理学抑制病毒逆转录酶活性可防止在苍蝇和大鼠神经元中观察到的退化表型。这些发现直接将内体功能障碍与没有 TDP-43 病理学的 FTD-ALS 模型中的 RV 去抑制联系起来。这些观察结果可能有助于理解先前在 ALS 患者中发现的 RV 激活。