TY  - JOUR
AU  - Menge, Sonja
AU  - Segura, Inmaculada
AU  - Hartmann, Max
AU  - Decker, Lorena
AU  - Kiran, Selin
AU  - Danzer, Karin M
AU  - Iben, Sebastian
AU  - Harbauer, Angelika B
AU  - Oeckl, Patrick
AU  - Freischmidt, Axel
TI  - Comparing loss of individual fragile X proteins suggests strong links to cellular senescence and aging.
JO  - Cellular and molecular life sciences
VL  - 82
IS  - 1
SN  - 1420-682X
CY  - Cham (ZG)
PB  - Springer International Publishing AG
M1  - DZNE-2025-01194
SP  - 358
PY  - 2025
AB  - Members of the fragile X protein (FXP) family (FMR1, FXR1 and FXR2) are differentially expressed in most types of cancer and major neurodegenerative diseases. While increased expression of FXR1 in cancer has been linked to senescence evasion and consequently tumor initiation and progression, decreased expression of FXPs in neurodegeneration may contribute to pathogenic protein aggregation and death of vulnerable neurons. However, due the causal role in fragile x syndrome, most data are available about loss of FMR1 in neurons while functions of FXR1 and especially FXR2 remain largely unexplored. To address this knowledge gap, and to directly compare functions of the FXPs, we used proteomics of CRISPR/Cas9 edited HAP1 cells carrying knockouts of the individual FXPs for identification of cellular mechanisms associated with these proteins. Further exploration of proteomic findings suggests roles of the FXPs in ribosome biogenesis, autophagy and mitochondrial health linked to organismal aging, and cellular senescence. Validation of FXP induced defects relevant for neurodegenerative diseases in neuroblastoma cell line SH-SY5Y upon FXP knockdown revealed high cell type specificity of individual FXP functions. Overall, we provide a comprehensive overview and comparison of cellular mechanisms related to the individual FXPs, as well as starting points for further studying this protein family in respective cell types of FXP associated diseases, and in aging in general.
KW  - Humans
KW  - Cellular Senescence: genetics
KW  - Fragile X Mental Retardation Protein: genetics
KW  - Fragile X Mental Retardation Protein: metabolism
KW  - Aging: genetics
KW  - Aging: metabolism
KW  - RNA-Binding Proteins: metabolism
KW  - RNA-Binding Proteins: genetics
KW  - CRISPR-Cas Systems
KW  - Autophagy
KW  - Cell Line, Tumor
KW  - Proteomics: methods
KW  - Mitochondria: metabolism
KW  - Fragile X Syndrome: metabolism
KW  - Fragile X Syndrome: genetics
KW  - Fragile X Syndrome: pathology
KW  - Neurodegenerative Diseases: metabolism
KW  - Neurodegenerative Diseases: genetics
KW  - Neurodegenerative Diseases: pathology
KW  - Alzheimer’s disease (Other)
KW  - Amyotrophic lateral sclerosis (Other)
KW  - Fragile x syndrome (Other)
KW  - Parkinson’s disease (Other)
KW  - Protein aggregation (Other)
KW  - Fragile X Mental Retardation Protein (NLM Chemicals)
KW  - RNA-Binding Proteins (NLM Chemicals)
KW  - FMR1 protein, human (NLM Chemicals)
KW  - FXR1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41117937
DO  - DOI:10.1007/s00018-025-05898-0
UR  - https://pub.dzne.de/record/281808
ER  -