TY  - JOUR
AU  - de Mello, Natalia Prudente
AU  - Berger, Michelle Tamara
AU  - Lagerborg, Kim A
AU  - Yan, Yingfei
AU  - Wettmarshausen, Jennifer
AU  - Keipert, Susanne
AU  - Weidner, Leopold
AU  - Tokarz, Janina
AU  - Möller, Gabriele
AU  - Ciciliot, Stefano
AU  - Walia, Safal
AU  - Cheng, Yiming
AU  - Chudenkova, Margarita
AU  - Artati, Anna
AU  - Weisenhorn, Daniela Vogt
AU  - Wurst, Wolfgang
AU  - Adamski, Jerzy
AU  - Nilsson, Roland
AU  - Cossu, Giovanni
AU  - Boon, Agnita
AU  - Kievit, Anneke
AU  - Mandemakers, Wim
AU  - Bonifati, Vincenzo
AU  - Jain, Mohit
AU  - Jastroch, Martin
AU  - Schmitt-Kopplin, Philippe
AU  - Perocchi, Fabiana
AU  - Dyar, Kenneth Allen
TI  - Pervasive glycative stress links metabolic imbalance and muscle atrophy in early-onset Parkinson's disease.
JO  - Molecular metabolism
VL  - 97
SN  - 2212-8778
CY  - Oxford [u.a.]
PB  - Elsevier
M1  - DZNE-2025-00677
SP  - 102163
PY  - 2025
AB  - Parkinson's disease (PD) is recognized as a systemic condition, with clinical features potentially modifiable by dietary intervention. Diets high in saturated fats and refined sugars significantly increase PD risk and exacerbate motor and non-motor symptoms, yet precise metabolic mechanisms are unclear. Our objective here was to investigate the interplay between diet and PD-associated phenotypes from a metabolic perspective.We explored PARK7 KO mice under chronic glycative stress induced by prolonged high-fat high-sucrose (HFHS) diet. We investigated metabolic consequences by combining classical metabolic phenotyping (body composition, glucose tolerance, indirect calorimetry, functional assays of isolated mitochondria) with metabolomics profiling of biospecimens from mice and PD patients.We found this obesogenic diet drives loss of fat and muscle mass in early-onset PD mice, with a selective vulnerability of glycolytic myofibers. We show that PD mice and early-onset familial PD patients are under pervasive glycative stress with pathological accumulation of advanced glycation end products (AGEs), including N-α-glycerinylarginine (α-GR) and N-α-glycerinyllysine (α-GK), two previously unknown glycerinyl-AGE markers.Our results offer the first proof for a direct link between diet, accumulation of AGEs and genetics of PD. We also expand the repertoire of clinically-relevant glycative stress biomarkers to potentially define at-risk patients before neurological or metabolic symptoms arise, and/or to monitor disease onset, progression, and effects of interventions.
KW  - Animals
KW  - Mice
KW  - Parkinson Disease: metabolism
KW  - Humans
KW  - Male
KW  - Diet, High-Fat: adverse effects
KW  - Muscular Atrophy: metabolism
KW  - Mice, Knockout
KW  - Glycation End Products, Advanced: metabolism
KW  - Female
KW  - Mice, Inbred C57BL
KW  - Metabolomics: methods
KW  - Muscle, Skeletal: metabolism
KW  - Disease Models, Animal
KW  - Advanced glycation endproducts (AGEs) (Other)
KW  - Biomarkers (Other)
KW  - Glycative stress (Other)
KW  - Glycobiology (Other)
KW  - Muscle atrophy (Other)
KW  - Parkinson's disease (Other)
KW  - Glycation End Products, Advanced (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40345387
DO  - DOI:10.1016/j.molmet.2025.102163
UR  - https://pub.dzne.de/record/279047
ER  -