A new study has identified a novel mechanism in the brain, which could potentially be linked to the onset of Alzheimer's and Parkinson's diseases. Published in the journal Brain, the research from the Scripps Research Institute (TSRI) has discovered a killing mechanism that could underpin a range of some of the most intractable neurodegenerative diseases such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ALS).
The work revealed the mechanism of toxicity of a misfolded form of the protein that underlies prion diseases, such as bovine spongiform encephalopathy (mad cow disease) and its human equivalent - Creutzfeldt-Jakob disease.
Professor at TSRI Corinne Lasmézas said the study reveals a novel mechanism, which causes the death of neurons in diseases like Alzheimer's where proteins misfold.
"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," she said.
In the new study, the team used a misfolded form of the prion disease protein, called TPrP, a model that had been previously created, to examine the behaviour of misfolded protein-induced neurodegeneration in the laboratory.
The researchers used biochemical techniques to demonstrate that TPrP induces neuronal death by significantly reducing the levels of NAD+ (nicotinamide adenine dinucleotide), which is common in all cells and key for energy production and cellular homeostasis.
By restoring NAD+, the team found that neurons could be rescued from TPrP injury. Even when administered a few days after TPrP exposure, an infusion of NAD+ reversed the damage within a number of hours.
"Our study shows for the first time that a failure of NAD+ metabolism is the cause of neuronal loss following exposure to a misfolded protein," Dr Lasmézas said.
A drop in NAD+ also triggers autophagy, which sees cells get rid of damaged material such as misfolded proteins, and apoptosis - programmed cell death when everything has gone awry. The researchers found that these mechanisms do not initiate the neuronal demise.
"We show that apoptosis or programmed cell death and autophagy are not primary players in the death cascade," said staff scientist Minghai Zhou, the first author of the study. "Modulation of neither of these processes significantly alters the death of TPrP-exposed neurons. This is all caused by NAD+ disappearing--the cell cannot survive without it."
Dr Lasmézas noted the loss of NAD+ is suggestive of some other neurodegenerative diseases, such as Parkinson's where NAD+ depletion could play a role in mitochondrial failure.
Posted by Philip Briggs
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