Buck Silas A, Mabry Samuel J, Glausier Jill R, Banks-Tibbs Tabitha, Ward Caroline, Kozel Jenesis, Fu Chen, Fish Kenneth N, Lewis David A, Logan Ryan W, Freyberg Zachary
Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.
Mol Psychiatry. 2025 Jan 29. doi: 10.1038/s41380-025-02909-1.
Age-related dopamine (DA) neuron loss is a primary feature of Parkinson's disease. However, whether similar biological processes occur during healthy aging, but to a lesser degree, remains unclear. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no difference in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (Th), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (Vglut2) mRNA expression. In co-transmitting Th/Vglut2 neurons, Th and Vglut2 transcripts decreased with aging. However, Th and Vglut2 protein levels in striatal synaptic release sites (e.g., terminals and axonal projections) did not differ throughout aging. Similar to the mouse, an initial study of human brain showed no effect of aging on midbrain neuron number with a concomitant decrease in TH and VGLUT2 mRNA expression. Unlike in mice, the density of striatal TH dopaminergic terminals was lower in aged human subjects. However, TH and VGLUT2 protein levels were unaffected in the remaining striatal boutons. Finally, in contrast to Th and Vglut2 mRNA, expression of most ribosomal genes in Th neurons was either maintained or even upregulated during aging. This suggests a homeostatic mechanism where age-related declines in transcriptional efficiency are overcome by ongoing ribosomal translation. Overall, we demonstrate species-conserved transcriptional effects of aging in midbrain dopaminergic and glutamatergic neurons that are not accompanied by marked cell death or lower striatal protein expression. This opens the door to novel therapeutic approaches to maintain neurotransmission and bolster neuronal resilience.
与年龄相关的多巴胺（DA）神经元损失是帕金森病的主要特征。然而，类似的生物学过程在健康衰老过程中是否也会发生，只是程度较轻，目前尚不清楚。因此，我们确定了中脑DA神经元在小鼠和人类衰老过程中是否会退化。在小鼠中，我们发现整个衰老过程中中脑神经元数量没有差异。尽管如此，我们发现中脑酪氨酸羟化酶（Th）的mRNA表达随年龄增长而下降，Th是DA合成的限速酶。在中脑谷氨酸能细胞中，我们同样发现囊泡谷氨酸转运体2（Vglut2）的mRNA表达随年龄增长而下降。在共表达Th/Vglut2的神经元中，Th和Vglut2转录本随衰老而减少。然而，纹状体突触释放部位（如终末和轴突投射）的Th和Vglut2蛋白水平在整个衰老过程中没有差异。与小鼠类似，一项对人类大脑的初步研究表明，衰老对中脑神经元数量没有影响，同时TH和VGLUT2的mRNA表达下降。与小鼠不同的是，老年人类受试者纹状体TH多巴胺能终末的密度较低。然而，其余纹状体突触小体中的TH和VGLUT2蛋白水平未受影响。最后，与Th和Vglut2 mRNA相反，Th神经元中大多数核糖体基因的表达在衰老过程中要么保持不变，甚至上调。这表明存在一种稳态机制，即持续的核糖体翻译克服了与年龄相关的转录效率下降。总体而言，我们证明了衰老对中脑多巴胺能和谷氨酸能神经元的转录影响在物种间具有保守性，且不伴有明显的细胞死亡或纹状体蛋白表达降低。这为维持神经传递和增强神经元弹性的新型治疗方法打开了大门。
