Buck Silas A, Mabry Samuel J, Glausier Jill R, Banks-Tibbs Tabitha, Ward Caroline, Kozel Jenesis Gayden, 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.
bioRxiv. 2024 Jun 1:2024.06.01.596950. doi: 10.1101/2024.06.01.596950.
Age-related dopamine (DA) neuron loss is a primary feature of Parkinson's disease. However, it remains unclear whether similar biological processes occur during healthy aging, albeit to a lesser degree. We therefore determined whether midbrain DA neurons degenerate during aging in mice and humans. In mice, we identified no changes in midbrain neuron numbers throughout aging. Despite this, we found age-related decreases in midbrain mRNA expression of tyrosine hydroxylase (), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 () mRNA expression. In co-transmitting / neurons, and transcripts decreased with aging. Importantly, striatal Th and Vglut2 protein expression remained unchanged. In translating our findings to humans, we found no midbrain neurodegeneration during aging and identified age-related decreases in and mRNA expression similar to mouse. Unlike mice, we discovered diminished density of striatal TH dopaminergic terminals in aged human subjects. However, TH and VGLUT2 protein expression were unchanged in the remaining striatal boutons. Finally, in contrast to and mRNA, expression of most ribosomal genes in 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）神经元丢失是帕金森病的主要特征。然而，目前尚不清楚在健康衰老过程中是否会发生类似的生物学过程，尽管程度较轻。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变化。尽管如此，我们发现与年龄相关的中脑酪氨酸羟化酶（）mRNA表达下降，酪氨酸羟化酶是DA合成的限速酶。在中脑谷氨酸能细胞中，我们同样发现与年龄相关的囊泡谷氨酸转运体2（）mRNA表达下降。在共同传递/的神经元中，和转录本随着衰老而减少。重要的是，纹状体中的Th和Vglut2蛋白表达保持不变。将我们的研究结果应用于人类时，我们发现在衰老过程中没有中脑神经变性，并确定了与年龄相关的和mRNA表达下降，与小鼠相似。与小鼠不同的是，我们发现老年人类受试者纹状体TH多巴胺能终末的密度降低。然而，TH和VGLUT2蛋白表达在其余纹状体突触小体中没有变化。最后，与和mRNA相反，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，即通过持续的核糖体翻译克服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治疗方法打开了大门。
