Translational Remodeling of the Synaptic Proteome During Aging

Cinzia Caterino  ¹ , Martino Ugolini  ^{2   3} , William Durso  ¹ , Kristina Jevdokimenko  ⁴ , Marco Groth  ¹ , Konstantin Riege  ¹ , Matthias Görlach  ¹ , Eugenio Fornasiero  ^{4   5} , Alessandro Ori  ¹ , Steve Hoffmann  ¹ , Alessandro Cellerino  ^{1   6}

Aging Cell. 2025 Oct 16:e70262. doi: 10.1111/acel.70262. Online ahead of print.

• PMID: 41099377
• DOI: 10.1111/acel.70262

Abstract

An important hallmark of aging is the loss of proteostasis, which can lead to the formation of protein aggregates and mitochondrial dysfunction in neurons. Although it is well known that protein synthesis is finely regulated in the brain, especially at synapses, where mRNAs are locally translated in an activity-dependent manner, little is known as to the changes in the synaptic proteome and transcriptome during aging. Therefore, this work aims to elucidate the relationship between the transcriptome and proteome at the soma and synaptic levels during aging. Proteomic and transcriptomic data analysis reveal that, in young animals, proteins and transcripts are correlated and synaptic regulation is driven by changes in the soma. During aging, there is a decoupling between transcripts and proteins and between somatic and synaptic compartments. Furthermore, the soma-synapse gradient of ribosomal genes changes upon aging, that is, ribosomal transcripts are less abundant and ribosomal proteins are more abundant in the synaptic compartment of old mice with respect to younglings. Additionally, transcriptomics data highlight a difference in the splicing of certain synaptic mRNA with aging. Taken together, our data provide a valuable resource for the study of the aging synapse.