NR as a Potential Neuroprotective Therapy for Parkinson's Disease
Introduction
Parkinson's disease (PD), known as the silent killer, has emerged as the second most common chronic neurodegenerative disease in the world after Alzheimer's disease, affecting 1-2% of the population across the world. Strikingly, nicotinamide riboside (NR), a precursor and exogenous supplement of nicotinamide adenine dinucleotide (NAD+), has been uncovered to be a candidate in alleviating PD via the regulation of glucose metabolism and the relief of endoplasmic reticulum stress (ERS).About PD
PD, first systematically described by the British physician James Parkinson, is a neurodegenerative disease, showing the clinical motor symptoms (resting tremor, rigidity, bradykinesia, postural instability, etc.) and non-motor symptoms (sleep disorders, olfactory disorders, autonomic dysfunction, cognitive/psychiatric disorders, etc.). The typical pathological characteristics of PD involve the progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein, leading to the formation of Lewy bodies in neurons. PD patients are often accompanied with the biochemical alterations of reduced dopamine transmission in striatal region as well as imbalance between dopamine and acetylcholine transmission. It may be related to many factors such as heredity, environment and aging of nervous system.The construction of an MPTP-induced zebrafish PD model
The zebrafish model shows great merits in the study of neurological diseases including PD. Herein, the establishment of the PD model is conducted by exposing zebrafish embryos (24-120 hpf) to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxic compound that damages DA neurons to induce Parkinsonian symptoms. Meanwhile, NR intervention (24-120 hpf; 48-120 hpf; 72-120 hpf) is carried out to evaluate its potential effect on PD.
Morphological alterations in the MPTP-induced zebrafish model post NR treatment
Morphologically, there are significant motor neuron aberrations (e.g. neurite shortening, deletion, and disorganization) in MPTP-treated zebrafish larvae, which however are improved in the NR-treated group. In addition, the endoplasmic reticulum lumen of zebrafish myoblasts in the MPTP-treated group appears to be swollen, with flat vesicles dilated and even vacuoles formed, but the morphology of the swollen endoplasmic reticulum lumen partially recovers following NR treatment.
Neuroprotective effects and molecular mechanisms of NR on the MPTP-induced PD zebrafish model
In the MPTP-affected PD zebrafish model, NR improves motor dysfunction, survival time, dopamine neurons, peripheral neurons and the NAD+/NADH level, regulates glycolysis as well as gluconeogenesis, and attenuates the ER stress.
Mechanically, the neuroprotective effect of NR in the PD zebrafish model may be realized by modulation of glucose metabolism and ERS via the Perk-Eif2α-Atf4-Chop pathway. Concretely, the NR treatment offsets the MPTP-induced changes in the expression levels of key enzymes related to the glucose metabolic pathway (pck1 ↓, g6pca.1↓, pklr ↑, gck ↑) and ER signaling pathway (Perk ↓, Eif2α ↓, Atf4 ↓, Chop↓).
