Researchers at the Florida Campus of The Scripps Research Institute (TSRI) recently discovered a mechanism responsible for neuronal death that could be linked to several neurodegenerative diseases like Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS). Their findings entitled “Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment” were published in the journal Brain.
Prion diseases are a family of rare, progressive neurodegenerative disorders that are caused by prions – abnormal, pathogenic agents able to induce anomalous folding of specific proteins usually in the brain. Bovine spongiform encephalopathy (also known as “mad cow disease”) and its human equivalent, Creutzfeldt-Jakob disease are examples of prion diseases.
Neurodegenerative disorders result from abnormalities in the processing of specific neuronal proteins. Neuronal death is a natural process, part of the brain development, that when not properly regulated can lead to neurodegenerative diseases. The mechanisms underlying neuronal death in protein misfolding neurodegenerative diseases like Parkinson’s, Alzheimer’s and prion diseases are unknown.
In the study, researchers used a model of a toxic misfolded form of the prion disease protein, named TPrP (toxic prion protein), in order to assess the neurodegeneration induced by misfolded proteins. The team found that the protein TPrP stimulates neuronal death by a massive depletion of NAD+ (nicotinamide adenine dinucleotide), which is a coenzyme required for energy production and cellular homeostasis. Reestablishing NAD+ levels is crucial for the rescue of neurons. Remarkably, researchers found that an infusion of NAD+, even when provided three days after TPrP exposure, was able to reverse neuronal fate within a few hours.
“Our study reveals a novel mechanism of neuronal death involved in a neurodegenerative protein-misfolding disease,” said the senior author of the study Dr. Corinne Lasmézas in a news release. “Importantly, the death of these cells is preventable. In our study, ailing neurons in culture and in an animal model were completely rescued by treatment, despite the continued presence of the toxic misfolded protein. This work suggests treatment strategies for prion diseases – and possibly other protein misfolding diseases such as Alzheimer’s.”
Regarding the death cascade observed in TPrP-exposed neurons, the first author of the study Dr. Minghai Zhou claimed that it “is all caused by NAD+ disappearing – the cell cannot survive without it.”
Researchers showed for the first time that a lack in NAD+ is responsible for the neuronal loss after exposure to a misfolded protein, and that this mechanism is likely to also occur in neurodegenerative diseases. Recently, the National Institute of Neurological Disorders and Stroke (NINDS) granted the team $1.4 million for further studies aiming to find potential drug candidates that are capable of restoring NAD+ levels for protection in prion diseases and eventually also applicable in other neurodegenerative diseases linked to protein misfolding.