PhD Scientific Days 2025

Poster Session I. - I: Theoretical and Translational Medicine

Studying neuronal autophagy in human ageing using induced neurons directly reprogrammed from adult human fibroblasts

Name of the presenter

Zsoldos Roland

Institute/workplace of the presenter

Institute of Translational Medicine

Authors

Roland Zsoldos^1,2, Chandramouli Muralidharan³, Anna Anoir Abbas¹, Balázs Kis¹, Kinga Vörös¹, Ágnes Varga¹, Ármin Sőth¹, Zsófia Koltai¹, Anikó Göblös⁴, Jenny J. Johansson³, Lajos Kemény⁴, Johan Jakobsson³, Karolina Pircs^1,2,3

1: HCEMM-SU Neurobiology and Neurodegenerative Diseases Research Group, Semmelweis University, Budapest, HU
2: HUN-REN-SZTAKI-SU Rejuvenation Research Group, Budapest, HU
3: Laboratory of Molecular Neurogenetics, Lund University, Lund, SE
4: HCEMM-Szeged University, Szeged, HU

Text of the abstract

Age is the major risk factor for most neurodegenerative diseases (NDDs), such as Alzheimer’s (AD). The molecular mechanisms that underlie aging and its contribution to NDDs remains largely unknown. Autophagy, a key pathway that controls the cytoplasmic homeostasis, declines with age and plays an instrumental role in age-related NDDs. The purpose of this project is to understand, using directly reprogrammed neurons obtained from human fibroblasts, how autophagy is affected during neuronal aging. We will analyze induced neurons (iNs) obtained from 63 healthy donors of young and old ages and perform detailed molecular, biochemical investigations of aging and the alterations of autophagy, using RNA-seq, DNA-methylation array, mass-spectrometry and metabolomic analysis. Our preliminary results indicate that iNs obtained using direct reprogramming retain age-associated features. The age of the donor strongly correlates with the predicted epigenetic age of the iNs. Our preliminary findings indicate that the transcriptional and posttranscriptional control of autophagy is altered with age in iNs. We went further studying basal and stress (starvation) induced autophagic mechanism, first results indicate different effect of starvation and autophagy response in iNs derived from differentially aged donors. This project will provide new insights into human neuronal aging, thereby opening for the design of new treatment strategies to restore autophagy alterations in aged neurons from patients with NDDs.

This work was also supported by the SE 250+ PhD Excellence Grant, SE250-2025-36 by Semmelweis University.