Deacidification of endolysosomes by neuronal aging drives synapse loss.

IF 3.6 3区 生物学 Q3 CELL BIOLOGY Traffic Pub Date : 2023-08-01 DOI:10.1111/tra.12889
Tatiana Burrinha, César Cunha, Michael J Hall, Mafalda Lopes-da-Silva, Miguel C Seabra, Cláudia Guimas Almeida
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引用次数: 2

Abstract

Previously, we found that age-dependent accumulation of beta-amyloid is not sufficient to cause synaptic decline. Late-endocytic organelles (LEOs) may be driving synaptic decline as lysosomes (Lys) are a target of cellular aging and relevant for synapses. We found that LAMP1-positive LEOs increased in size and number and accumulated near synapses in aged neurons and brains. LEOs' distal accumulation might relate to the increased anterograde movement in aged neurons. Dissecting the LEOs, we found that late-endosomes accumulated while there are fewer terminal Lys in aged neurites, but not in the cell body. The most abundant LEOs were degradative Lys or endolysosomes (ELys), especially in neurites. ELys activity was reduced because of acidification defects, supported by the reduction in v-ATPase subunit V0a1 with aging. Increasing the acidification of aged ELys recovered degradation and reverted synaptic decline, while alkalinization or v-ATPase inhibition, mimicked age-dependent Lys and synapse dysfunction. We identify ELys deacidification as a neuronal mechanism of age-dependent synapse loss. Our findings suggest that future therapeutic strategies to address endolysosomal defects might be able to delay age-related synaptic decline.

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神经元老化导致内溶酶体脱酸,导致突触丢失。
先前,我们发现β -淀粉样蛋白的年龄依赖性积累不足以引起突触衰退。由于溶酶体(Lys)是细胞衰老的靶点,与突触相关,晚期内吞细胞器(LEOs)可能会导致突触的衰退。我们发现,在衰老的神经元和大脑中,lamp1阳性的LEOs的大小和数量增加,并在突触附近积聚。LEOs远端积累可能与老龄神经元逆行运动增加有关。通过对LEOs的解剖,我们发现在衰老的神经突中晚期核内体积累,而终末赖氨酸较少,但在细胞体中没有。最丰富的LEOs是降解赖氨酸或内溶酶体(ELys),尤其是在神经突中。随着年龄的增长,v-ATPase亚基V0a1的减少也支持了ELys活性的降低。增加衰老的赖氨酸酸化可以恢复退化和恢复突触衰退,而碱化或v- atp酶抑制则模拟年龄依赖性赖氨酸和突触功能障碍。我们确定ELys脱酸是年龄依赖性突触丧失的神经元机制。我们的研究结果表明,未来解决内溶酶体缺陷的治疗策略可能能够延缓与年龄相关的突触衰退。
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来源期刊
Traffic
Traffic 生物-细胞生物学
CiteScore
8.10
自引率
2.20%
发文量
50
审稿时长
2 months
期刊介绍: Traffic encourages and facilitates the publication of papers in any field relating to intracellular transport in health and disease. Traffic papers span disciplines such as developmental biology, neuroscience, innate and adaptive immunity, epithelial cell biology, intracellular pathogens and host-pathogen interactions, among others using any eukaryotic model system. Areas of particular interest include protein, nucleic acid and lipid traffic, molecular motors, intracellular pathogens, intracellular proteolysis, nuclear import and export, cytokinesis and the cell cycle, the interface between signaling and trafficking or localization, protein translocation, the cell biology of adaptive an innate immunity, organelle biogenesis, metabolism, cell polarity and organization, and organelle movement. All aspects of the structural, molecular biology, biochemistry, genetics, morphology, intracellular signaling and relationship to hereditary or infectious diseases will be covered. Manuscripts must provide a clear conceptual or mechanistic advance. The editors will reject papers that require major changes, including addition of significant experimental data or other significant revision. Traffic will consider manuscripts of any length, but encourages authors to limit their papers to 16 typeset pages or less.
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