Muscle and motor neuron disorders, Parkinson’s disease and other movement disorders

Publication date: 14/05/2025

Authors: Szegő, É.M., Höfs, L., Antoniou, A. et al.

Journal: Nat Commun 16, 4470

Commentary: The study by Éva M Szegő and colleagues investigates the neuroprotective potential of intermittent fasting (IF) in a mouse model of Parkinson’s disease (PD) induced by the overexpression of mutant α-synuclein (A53T-aSyn) through injection of serotype 2/7 rAAV into the substantia nigra (SN). At the 4-week time point after the injection, a 4-week alternate-day fasting regimen was established, leading to a significantly reduced dopaminergic neuron and axon degeneration, preserved dopamine levels and synaptic density, and enhanced motor performance. Mechanistically, IF enhanced autophagy, facilitated the clearance of pathological phosphorylated α-synuclein species, and decreased their accumulation in insoluble brain fractions. Transcriptomic analyses indicated that IF modulated inflammatory and microglial gene expression, an effect confirmed in primary neuronal and glial cultures where IF-related pathways affected α-synuclein toxicity and neuroinflammation. This study provides in vivo evidence that intermittent fasting can reduce synuclein pathology and protect against cognitive decline in a model of PD. These findings reveal a novel, non-pharmacological approach to mitigate neurodegeneration in synucleinopathies.

Commented by: Gioia Marino (20/06/2025)

DOI: https://doi.org/10.1038/s41467-025-59249-5