High-fat high-sucrose diet exacerbates muscle atrophy in PARK7 KO mice, a model of early-onset parkinsonism.

Atrophy of glycolytic 2B myofibers is associated with accumulation of advanced glycation endproducts (AGEs).

Identification of 2 novel arginine and lysine amide-AGEs in tissues and biofluids of PARK7 KO mice.

Novel amide-AGEs distinguish patient fibroblasts with PARK7 KO early-onset Parkinson's disease from healthy controls.

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.

Parkinson's disease

Muscle atrophy

Glycobiology

Glycative stress

Advanced glycation endproducts (AGEs)

Biomarkers

© 2025 The Authors. Published by Elsevier GmbH.