Aging disrupts the coordination between mRNA and protein expression in mouse and human midbrain

• Published in: Molecular psychiatry Vol. 30; no. 7; pp. 3039 - 3054
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2025; Nature Publishing Group
• Subjects: 14/19; 14/32; 38; 38/91; 631/1647; 631/378; 64; 64/60; 82; 82/51; Adult; Aged; Aged, 80 and over; Aging; Aging - genetics; Aging - metabolism; Animals; Behavioral Sciences; Biological Psychology; Biosynthesis; Brain research; Cell death; Corpus Striatum - metabolism; Dopamine - metabolism; Dopamine receptors; Dopaminergic Neurons - metabolism; Female; Females; Gene expression; Glutamatergic transmission; Glutamic acid transporter; Human subjects; Humans; Hybridization; Insects; Male; Males; Medicine; Medicine & Public Health; Mesencephalon; Mesencephalon - metabolism; Mice; Mice, Inbred C57BL; Middle age; Middle Aged; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - metabolism; Neurosciences; Neurotransmission; Parkinson's disease; Pharmacotherapy; Presynapse; Protein expression; Proteins; Psychiatry; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; Vesicular Glutamate Transport Protein 2 - genetics; Vesicular Glutamate Transport Protein 2 - metabolism
• ISSN: 1359-4184; 1476-5578; 1476-5578
• 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.