Nicotinamide Riboside (NR) and Parkinson's Disease: Time- and Context-Dependent Effects on Brain and Gut Pathology in a Transgenic Mouse Model

Abstract

Parkinson’s Disease (PD) is characterized by alpha-synuclein overexpression, neuroinflammation, and dopaminergic neuron loss. Among its pathogenic mechanisms, mitochondrial dysfunction and oxidative stress play a central role, driving protein aggregation, inflammation, and ultimately neuronal death. Therefore, mitochondrial dysfunction represents a promising target for therapeutic intervention. Nicotinamide riboside (NR), a NAD+ precursor, is an emerging potential therapeutic strategy to enhance mitochondrial activity. However, there is a lack of in vivo research, particularly regarding gut pathophysiology, considering the emerging relevance of the gut-brain axis in PD progression. We investigated the effects of NR supplementation in a transgenic mouse model overexpressing full-length alpha-synuclein under the Thy1-SNCA gene promoter (Thy1-asyn). The study was conducted at two different timepoints to evaluate the time-dependent effects of NR on brain and colon tissues of a mouse model exhibiting PD-like pathology.

NR supplementation improved motor function in Thy1-asyn mice independently of the intervention time, despite no detectable changes in dopaminergic neuron (TH+) quantification. In both WT and Thy1-asyn mice, early NR treatment increased alpha-synuclein expression in the brain, while late treatment enhanced its expression in the colon, possibly reflecting protein clearance imbalance. NR also increased cell ramification in early-treated mice, highlighting a potential neuroprotective response. Elevated GFAP expression at both timepoints indicated increased neuroinflammation in NR-treated mice compared to the vehicle-treated ones, suggesting a transient inflammatory response possibly leading to resolution. Lastly, NR reduced Claudin-3 expression in early-treated WT mice, whereas it enhanced its expression in the late treatment, suggesting a time-dependent modulation of the intestinal barrier integrity and gut-associated neuroinflammation linked to barrier restoration and recovery. Our findings highlight the context-dependent effects of NR in PD –modulated by timing, phenotype, and treatment – underscoring the complexity and the need for further targeted research.