Formation of Reticulon 3 (RTN3)-immunoreactive dystrophic neurites (RIDNs) occurs early during the growth of amyloid plaques in Alzheimer's disease (AD) brains. We have shown that RIDNs in AD and aging mouse brains are composed of abnormally clustered tubular endoplasmic reticulum (ER) and degenerating mitochondria. To understand RTN3-mediated abnormal tubular ER clustering, we aimed to identify proteins that interact with RTN3 and impact accumulation of tubular ER in RIDNs. We found that the N-terminal domain of RTN3, which is unique among RTN family members, specifically interacted with dynactin 6 (DCTN6), a protein involved in dynein-mediated retrograde transport of cargo vesicles. DCTN6 protein levels decrease with aging in the hippocampal regions of WT mice. We found that DCTN6 deficiency enhanced RTN3 protein levels, high molecular weight RTN3 levels, and hippocampus-specific RIDN formation in aging brains of transgenic mice overexpressing RTN3. Our results suggest that the DCTN6-RTN3 interaction mediates tubular ER trafficking in axons, and a DCTN6 deficiency in the hippocampus impairs axonal ER trafficking, leading to abnormal ER accumulation and RIDN formation in brains of aging mice.

Reticulon 3 (RTN3)-免疫反应性营养不良神经突 (RIDN) 的形成发生在阿尔茨海默病 (AD) 大脑中淀粉样斑块生长的早期。我们已经证明 AD 和衰老小鼠大脑中的 RIDN 由异常聚集的管状内质网 (ER) 和退化的线粒体组成。为了了解 RTN3 介导的异常肾小管 ER 聚集，我们旨在鉴定与 RTN3 相互作用并影响 RIDN 中肾小管 ER 积累的蛋白质。我们发现 RTN3 的 N 末端结构域在 RTN 家族成员中是独一无二的，它与 dynactin 6 (DCTN6) 相互作用，这是一种参与动力蛋白介导的货物囊泡逆行运输的蛋白质。DCTN6 蛋白水平随着 WT 小鼠海马区的衰老而降低。我们发现 DCTN6 缺乏会提高 RTN3 蛋白水平，高分子量 RTN3 水平，以及过表达 RTN3 的转基因小鼠衰老大脑中海马特异性 RIDN 的形成。我们的研究结果表明，DCTN6-RTN3 相互作用介导轴突中管状 ER 运输，海马中 DCTN6 缺乏会损害轴突 ER 运输，导致衰老小鼠大脑中异常 ER 积累和 RIDN 形成。