Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress

Kevin Rhine; Rachel Li; Hema M Kopalle; Katherine Rothamel; Xuezhen Ge; Elle Epstein; Orel Mizrahi; Assael A Madrigal; Hsuan-Lin Her; Trent A Gomberg; Anita Hermann; Joshua L Schwartz; Amanda J Daniels; Uri Manor; John Ravits; Robert A J Signer; Eric J Bennett; Gene W Yeo

doi:10.1038/s41593-025-01952-z

Neuronal aging causes mislocalization of splicing proteins and unchecked cellular stress

Nat Neurosci. 2025 Jun;28(6):1174-1184. doi: 10.1038/s41593-025-01952-z. Epub 2025 Jun 2.

Authors

Kevin Rhine^{1

2

3

4}, Rachel Li^{1

2

3

5}, Hema M Kopalle^{1

2

3

6}, Katherine Rothamel^{1

2

3

7}, Xuezhen Ge⁸, Elle Epstein^{1

2

3}, Orel Mizrahi^{1

2

3}, Assael A Madrigal^{1

2

3}, Hsuan-Lin Her^{1

2

3

9}, Trent A Gomberg^{1

2

3

5}, Anita Hermann¹⁰, Joshua L Schwartz^{1

2

3}, Amanda J Daniels^{2

8

11}, Uri Manor^{4

8}, John Ravits¹⁰, Robert A J Signer^{2

11}, Eric J Bennett⁸, Gene W Yeo^{12

13

14

15

16

17

18}

Affiliations

¹ Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
² Sanford Stem Cell Institute Innovation Center and Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.
³ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
⁴ Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA, USA.
⁵ Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
⁶ Biological Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
⁷ Center for RNA Technologies & Therapeutics, University of California San Diego, La Jolla, CA, USA.
⁸ Department of Cell & Developmental Biology, University of California San Diego, La Jolla, CA, USA.
⁹ Bioinformatics & Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA.
¹⁰ Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA, USA.
¹¹ Division of Regenerative Medicine, Department of Medicine, Sanford Stem Cell Institute, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
¹² Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA. geneyeo@ucsd.edu.
¹³ Sanford Stem Cell Institute Innovation Center and Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA. geneyeo@ucsd.edu.
¹⁴ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA. geneyeo@ucsd.edu.
¹⁵ Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA. geneyeo@ucsd.edu.
¹⁶ Biological Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA. geneyeo@ucsd.edu.
¹⁷ Center for RNA Technologies & Therapeutics, University of California San Diego, La Jolla, CA, USA. geneyeo@ucsd.edu.
¹⁸ Bioinformatics & Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA. geneyeo@ucsd.edu.

Abstract

Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins-like the dementia- and ALS-associated protein TDP-43-mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.

MeSH terms

Aged
Aging* / metabolism
Aging* / pathology
Animals
Cells, Cultured
Cellular Senescence* / physiology
DNA-Binding Proteins / metabolism
Fibroblasts / metabolism
Humans
Mice
Mice, Inbred C57BL
Neurons* / metabolism
Neurons* / pathology
RNA-Binding Proteins* / metabolism
Stress, Physiological* / physiology

Substances

RNA-Binding Proteins
DNA-Binding Proteins

Abstract

MeSH terms

Substances

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