Silas A. Buck, Samuel J. Mabry, Jill R. Glausier, Tabitha Banks-Tibbs, Caroline Ward, Jenesis Kozel, Chen Fu, Kenneth N. Fish, David A. Lewis, Ryan W. Logan, Zachary Freyberg
{"title":"Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain","authors":"Silas A. Buck, Samuel J. Mabry, Jill R. Glausier, Tabitha Banks-Tibbs, Caroline Ward, Jenesis Kozel, Chen Fu, Kenneth N. Fish, David A. Lewis, Ryan W. Logan, Zachary Freyberg","doi":"10.1038/s41380-025-02909-1","DOIUrl":null,"url":null,"abstract":"<p>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 (<i>Th</i>), the rate limiting enzyme of DA synthesis. Among midbrain glutamatergic cells, we similarly identified age-related declines in vesicular glutamate transporter 2 (<i>Vglut2</i>) mRNA expression. In co-transmitting <i>Th</i><sup>+</sup>/<i>Vglut2</i><sup>+</sup> neurons, <i>Th</i> and <i>Vglut2</i> transcripts decreased with aging. However, Th and Vglut2 protein levels in striatal synaptic release sites (<i>e.g</i>., 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 <i>TH</i> and <i>VGLUT2</i> mRNA expression. Unlike in mice, the density of striatal TH<sup>+</sup> 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 <i>Th</i> and <i>Vglut2</i> mRNA, expression of most ribosomal genes in <i>Th</i><sup>+</sup> 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.</p>","PeriodicalId":19008,"journal":{"name":"Molecular Psychiatry","volume":"9 1","pages":""},"PeriodicalIF":9.6000,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41380-025-02909-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
期刊介绍:
Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.