Killing mechanism that can underpin Alzheimer's and Parkinson's diseases discovered

A team of scientists has for the first time discovered a killing mechanism that could underpin a range of the most intractable neurodegenerative diseases such as Alzheimer's, Parkinson's and ALS.

The new study 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.

Researcher Corinne Lasmezas from the Florida campus of The Scripps Research Institute (TSRI) said that the study reveals a novel mechanism of neuronal death involved in a neurodegenerative protein-misfolding disease.

Lasmezas added that importantly, the death of these cells is preventable and in their 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.

In the new study, the scientists used a misfolded form of the prion disease protein, called TPrP, a model they had previously developed, to study misfolded protein-induced neurodegeneration in the laboratory. Misfolded proteins are the common cause of the group of diseases comprising prion, Alzheimer's, Parkinson's diseases, ALS and other conditions.

Using biochemical techniques, the researchers demonstrated that TPrP induces neuronal death by profoundly depleting NAD+ (nicotinamide adenine dinucleotide), a metabolite well known as a coenzyme that is common to all cells and necessary for energy production and cellular homeostasis.

Restoring NAD+ proved to be the critical factor for the rescue of neurons subjected to TPrP injury. Even when added three days after TPrP exposure, an infusion of NAD+ reversed within only a few hours the fate of neurons that had been doomed to destruction.

The study shows for the first time that a failure of NAD+ metabolism is the cause of neuronal loss following exposure to a misfolded protein, said Lasmezas.

The study is published recently in the journal Brain.