Nicotinamide Riboside Enhances Mitochondrial Bioenergetics and Dopaminergic Signaling Independent of Neuron Survival in a Double-Hit Parkinson's Model.

BACKGROUND

Parkinson's disease (PD) is characterized by progressive degeneration of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the development of motor and non-motor impairments. Mitochondrial dysfunction, exacerbated by aging and environmental exposures, is a central contributor to PD pathogenesis. Nicotinamide riboside (NR), a dietary precursor of nicotinamide adenine dinucleotide (NAD+), enhances cellular bioenergetics and mitochondrial health, yet its translational potential for PD remains insufficiently defined.

METHODS

We used a "double-hit" PD mouse model combining A53T α-synuclein overexpression in SNc DA neurons with chronic dietary benomyl exposure. Mice received continuous NR supplementation in drinking water. Motor behavior was monitored longitudinally using open-field and rotarod assays. Striatal dopamine dynamics were quantified using genetically encoded fluorescent dopamine sensors to measure tonic and optogenetically evoked dopamine release. In vivo ATP/ADP ratios were measured in DA neurons and striatal spiny projection neurons (SPNs) using fiber photometry of the ratiometric sensor PercevalHR.

RESULTS

Chronic NR supplementation markedly improved motor performance in double-hit PD mice, despite failing to prevent SNc DA neuron degeneration. NR robustly increased both tonic and stimulus-evoked striatal dopamine release in control and PD mice. Additionally, NR elevated ATP/ADP ratios across multiple neuronal populations, indicating enhanced mitochondrial energetic capacity.

CONCLUSIONS

NR supplementation enhances DA neurotransmission and mitochondrial bioenergetics in vivo, conferring functional benefits that occur independently of DA neuron survival. These findings identify metabolic augmentation via NR as a promising adjunctive strategy for mitigating PD-related functional deficits.