Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, VD 1015 Lausanne, Switzerland.
Brain Mind Institute, EPFL - Swiss Federal Institute of Technology Lausanne, VD 1015 Lausanne, Switzerland.
Cell Rep. 2024 Jun 25;43(6):114256. doi: 10.1016/j.celrep.2024.114256. Epub 2024 May 24.
The decline of motor ability is a hallmark feature of aging and is accompanied by degeneration of motor synaptic terminals. Consistent with this, Drosophila motor synapses undergo characteristic age-dependent structural fragmentation co-incident with diminishing motor ability. Here, we show that motor synapse levels of Trio, an evolutionarily conserved guanine nucleotide exchange factor (GEF), decline with age. We demonstrate that increasing Trio expression in adult Drosophila can abrogate age-dependent synaptic structural fragmentation, postpone the decline of motor ability, and maintain the capacity of motor synapses to sustain high-intensity neurotransmitter release. This preservative activity is conserved in transgenic human Trio, requires Trio Rac GEF function, and can also ameliorate synapse degeneration induced by depletion of miniature neurotransmission. Our results support a paradigm where the structural dissolution of motor synapses precedes and promotes motor behavioral diminishment and where intervening in this process can postpone the decline of motor function during aging.
运动能力的下降是衰老的一个显著特征，伴随着运动突触末梢的退化。与此一致的是，果蝇的运动突触经历了特征性的与运动能力下降相一致的年龄依赖性结构碎片化。在这里，我们表明，进化上保守的鸟嘌呤核苷酸交换因子（GEF）Trio 的运动突触水平随年龄增长而下降。我们证明，在成年果蝇中增加 Trio 的表达可以消除年龄相关的突触结构碎片化，延缓运动能力的下降，并保持运动突触维持高强度神经递质释放的能力。这种保护作用在转基因人类 Trio 中是保守的，需要 Trio Rac GEF 功能，并且还可以改善由微小神经传递耗竭引起的突触退化。我们的研究结果支持这样一种范式，即运动突触的结构溶解先于并促进运动行为的减弱，而干预这一过程可以延缓衰老过程中运动功能的下降。
