Dynactin 6 deficiency enhances aging-associated dystrophic neurite formation in mouse brains

[摘要] 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 ag -ing mouse brains are composed of abnormally clustered tubular endoplasmic reticulum (ER) and degener-ating 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 defi-ciency 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. (c) 2021 Elsevier Inc. All rights reserved.

[发布日期] 2021-11-01

[关键词] Alzheimer's disease;Aging;Dystrophic neurites;Tubular ER;Reticulon;RTN3;Dynactin;DCTN6;Axonal transport