Modulation of NAD+ levels lead to neuroprotective effects in a Drosophila model of Parkinson’s disease

English physician James Parkinson wrote an Essay of the Shaking Palsy in 1817 describing the characteristic tremor, abnormal posture and walk, paralysis and muscle weakness, as well as the way the disease evolves over time. Between 1868 and 1881, early neurologists further contributed to providing a greater understanding of the disease. Jean-Martin Charcot, one of these early neurologists, is often regarded as “the founder of modern neurology”. His input was critical as he was able to establish a clear distinction between rigidity, diminished muscle strength, and slowness of movement. He was also the lead advocate for the renaming of the disease in honor of James Parkinson.

Parkinson’s disease (PD) affects one out of every 500 people. Most people who get PD are aged 50 or over, but younger people can be diagnosed with Parkinson’s. The disease is then referred to as early onset PD. Parkinson’s comes in two classifications: primary and secondary. Primary PD is deemed idiopathic, although some cases seem to have genetic origins. Secondary PD is environment-linked (e.g. caused by toxins). The death of cells in a region of the midbrain called the substantia nigra results in a drop of dopamine levels in this region and the development of motor symptoms. The actual reason behind the death of these cells is unknown but it is thought that the build-up of aggregated proteins into Lewy bodies in the neurons is involved in the process. Unfortunately, there is currently no cure for PD. Medications constitute mainly of levodopa (L-DOPA), dopamine agonists, and MAO-B inhibitors. These are especially useful during the early stages of the disease as they help with motor symptoms. When medications are no longer effective, surgery and brain stimulation can be considered. In later stages, quality of life is paramount and palliative care has to be provided.

Parkin is an E3 ubiquitin ligase with a major role in the quality control of the mitochondria. Parkin is thought to be an essential factor in the process of mitophagy, that is to say the autophagy of mitochondria. Mutations in the PARK2 gene, which encodes Parkin, lead to mitochondrial dysfunction and have been shown to induce PD via dopaminergic cell death. Drosophila melanogaster (the fruit fly) is a versatile model organism that has been used in biomedical research to study a broad range of phenomena including neurological disorders. Parkin-mutant flies represent a very convenient model as they exhibit symptoms analogous to those observed in patients with PD, namely mitochondrial dysfunction via drop of mitochondria membrane potential, muscle deterioration, and selective loss of dopaminergic cells in the brain.

Nicotinamide adenine dinucleotide (NAD⁺) is a key component involved in the production of cellular energy in the mitochondria and in DNA repair mechanisms as a co-factor for NAD⁺-dependent enzymes, such as PARP. Using Parkin-mutant flies, Dr. Lehmann and colleagues from the MRC Toxicology Unit in Leicester (UK) demonstrated that the supplement of nicotinamide, a NAD⁺ precursor, helped salvage mitochondrial function with increased levels of NAD⁺ and maintain mitochondria membrane potential. It also had neuroprotective effects by preventing loss of dopaminergic neurons. Enhanced oxidative stress is believed to trigger PARP, which uses and depletes cellular NAD⁺ stores in order to repair DNA damage. Levels of protein PARylation, a product of PARP activity, were found to be significantly augmented in Parkin-mutant flies. Using PARP- and Parkin-mutant flies, the authors of this study noticed the increase in NAD⁺ levels and its metabolites, as well as the rescue of both mitochondrial function and dopaminergic neuron loss. Altogether, these results demonstrate that administration of NAD⁺ precursor and/or the inhibition of NAD⁺-dependent enzymes, such as PARP, may be potent and interesting allies against PD by restoring mitochondrial function and preventing neuronal death.

Enzo Life Sciences offers a comprehensive product portfolio for advancing your research in Parkinson’s disease and in neuroscience including antibodies, ELISA kits, live cell analysis, recombinant proteins, and small molecules; some of which are described below.

Browse all our TechNotes by Interests

Apoptosis Autophagy Bioprocess Cancer Cell Death CGH Drug Discovery Endocrinology Inflammation Infographic

Immunity Immunohiostochemistry Metabolism Molecular Biology Neuroscience Oxidative Stress Proteasome Screening Stem Cells Toxicology We Are Enzo!

Never miss a new TechNote!

Receive our TechNotes as soon as they are published.