Krishna Meera M, Waghmare Swapnil G, Franitza Ariel L, Maccoux Emily C, E Lezi
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Aging Cell. 2025 Apr;24(4):e14459. doi: 10.1111/acel.14459. Epub 2024 Dec 27.
Despite advances in understanding molecular and cellular changes in the aging nervous system, the upstream drivers of these changes remain poorly defined. Here, we investigate the roles of non-neural tissues in neuronal aging, using the cutaneous PVD polymodal sensory neuron in Caenorhabditis elegans as a model. We demonstrate that during normal aging, PVD neurons progressively develop excessive dendritic branching, functionally correlated with age-related proprioceptive deficits. Our study reveals that decreased collagen expression, a common age-related phenomenon across species, triggers this process. Specifically, loss-of-function in dpy-5 or col-120, genes encoding cuticular collagens secreted to the epidermal apical surface, induces early-onset excessive dendritic branching and proprioceptive deficits. Adulthood-specific overexpression of dpy-5 or col-120 mitigates excessive branching in aged animals without extending lifespan, highlighting their specific roles in promoting neuronal health span. Notably, collagen reduction specifically drives excessive branching in select sensory neuron subclasses but does not contribute to PVD dendritic beading, another aging-associated neurodegenerative phenotype associated with distinct mechanosensitive dysfunction. Lastly, we identify that rig-3, an immunoglobulin superfamily member expressed in interneurons, acts upstream of collagen genes to maintain PVD dendritic homeostasis during aging, with collagen's regulatory role requiring daf-16/FOXO. These findings reveal that age-related collagen reduction cues neuronal aging independently of collagen's traditional structural support function, possibly involving bi-directional communication processes between neurons and non-neuronal cells. Our study also offers new insights into understanding selective neuron vulnerability in aging, emphasizing the importance of multi-tissue strategies to address the complexities of neuronal aging.
尽管在理解衰老神经系统中的分子和细胞变化方面取得了进展，但这些变化的上游驱动因素仍不清楚。在这里，我们以秀丽隐杆线虫的皮肤PVD多模态感觉神经元为模型，研究非神经组织在神经元衰老中的作用。我们证明，在正常衰老过程中，PVD神经元逐渐出现过度的树突分支，这与年龄相关的本体感觉缺陷在功能上相关。我们的研究表明，胶原蛋白表达的降低，这是一种跨物种常见的与年龄相关的现象，触发了这一过程。具体来说，dpy-5或col-120（编码分泌到表皮顶端表面的表皮胶原蛋白的基因）功能丧失会导致早发性过度树突分支和本体感觉缺陷。在成年期特异性过表达dpy-5或col-120可减轻老年动物的过度分支，但不会延长寿命，突出了它们在促进神经元健康寿命方面的特定作用。值得注意的是，胶原蛋白减少特异性地驱动特定感觉神经元亚类的过度分支，但不会导致PVD树突珠化，这是另一种与不同机械敏感功能障碍相关的衰老相关神经退行性表型。最后，我们确定rig-3（一种在中间神经元中表达的免疫球蛋白超家族成员）在衰老过程中在胶原蛋白基因上游起作用，以维持PVD树突的稳态，胶原蛋白的调节作用需要daf-16/FOXO。这些发现表明，与年龄相关的胶原蛋白减少提示神经元衰老独立于胶原蛋白的传统结构支持功能，可能涉及神经元和非神经元细胞之间的双向通讯过程。我们的研究还为理解衰老过程中选择性神经元易损性提供了新的见解，强调了多组织策略在解决神经元衰老复杂性方面的重要性。
