Prion disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia and amyotrophic lateral sclerosis all share a common etiology: neurodegeneration linked to the misfolding and aggregation of a specific protein. But the causes of neuronal death in these diseases are still poorly understood, impeding the development of strategies to prevent neurodegeneration. To fill this knowledge gap, Corinne Lasmézas (The Scripps Research Institute, Jupiter, FL) and her collaborators study neurodegeneration in prion disease using a highly toxic misfolded monomeric form of prion protein (TPrP).

They recently reported that TPrP induces neuronal death by depleting nicotinamide adenine dinucleotide (NAD+) in neurons. They also showed that neuronal death could be rescued in vitro and in vivo by replenishing NAD+ (Brain doi:10.1093/brain/awv002; published online 11 February 2015). “What we found is that if you replenish NAD in these neurons, it completely protects them against the injury caused by misfolded prion protein,” Lasmézas told Jon Hamilton of National Public Radio (http://www.npr.org/blogs/health/2015/03/09/390980364/mad-cow-research-hints-at-ways-to-halt-alzheimers-parkinsons). The results suggest that neurodegeneration in prion disease is reversible, raising hopes for new treatment strategies for these and other diseases associated with protein misfolding and aggregation.

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The researchers first examined the effects of TPrP on cultured neurons. Exposure to TPrP caused cell death and markedly reduced intracellular levels of NAD+, but restoring normal levels of NAD+ rescued the neurons. They subsequently assessed the effects of TPrP and NAD+ in vivo in C57BL/6 mice. TPrP induced extensive neuronal damage in the hippocampus, which was prevented by co-administration of NAD+. Finally, the researchers sought to determine whether NAD+ had similar neuroprotective effects in a mouse model of prion disease. Mice were given daily doses of NAD+ beginning either at the onset of the clinical phase or after symptoms had developed (117 d or 130 d after inoculation with prions, respectively). In both cases, NAD+ treatment slowed disease progression, improved activity and motor skills and delayed severe motor impairment and paralysis. NAD+ treatment did not prolong survival, however.

The study identifies NAD+ depletion as a cause of neurodegeneration induced by a misfolded protein. Moreover, the results show that neuronal death induced by NAD+ depletion is reversible and that NAD+ replenishment can alleviate neurodegeneration and preserve motor function in mice with prion disease. If it has similar effects in people with prion disease, NAD+ treatment could offer a way to improve their quality of life.