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

Autor:	Buck SA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Mabry SJ; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Glausier JR; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Banks-Tibbs T; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.; College of Medicine, The Ohio State University, Columbus, OH, USA., Ward C; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA., Kozel JG; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Fu C; Department of Psychiatry, University of Massachusetts Chan Medical School, Worcester, MA, USA., Fish KN; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Lewis DA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA., Logan RW; Department of Psychiatry, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Freyberg Z; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 01. Date of Electronic Publication: 2024 Jun 01.
DOI:	10.1101/2024.06.01.596950
Abstrakt:	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 ( 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. 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 TH and VGLUT2 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 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. Competing Interests: Conflicts of Interest The authors report no conflicts of interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu