Possible mechanism underpinning Alzheimer’s and Parkinson’s type diseases found

Neurodegenerative diseases have remained stubbornly increasing in prevalence for sometime now. Unfortunately longer life does not mean a better quality of life. Thankfully that could change sooner than you think, scientists have 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.

“Our study reveals a novel mechanism of neuronal death involved in a neurodegenerative protein-misfolding disease,” said Corinne Lasmézas, a TSRI professor who led the study.

“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.”

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.

“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,” Lasmézas said.

The loss of NAD+ also triggers autophagy — a way cells rid themselves of damaged material such as misfolded proteins — and apoptosis, or programmed cell death, the last resort of the cell when everything starts to go wrong. However, the researchers demonstrated 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.”

The team 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.

So what’s next, well a recent $1.4-million grant from the National Institute of Neurological Disorders and Stroke (NINDS) will support further work to look for drug candidates based on the new findings. The team has already developed several primary tests for compounds that could restore NAD+ and plan to begin those tests.

If all goes well we could see an alternative to the treatments available on the market now in a “short” 10 to 15 years, on the bright side that’s still soon enough for plenty of people still in the workforce today. The downside of course is the millions of people who suffer from a wide range of neurodegenerative diseases right now and their families — who really could use some good news.

Sources:
Minghai Zhou, Gregory Ottenberg, Gian Franco Sferrazza, Christopher Hubbs, Mohammad Fallahi, Gavin Rumbaugh, Alicia F. Brantley, & Corinne I. Lasmézas (2015). Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment Brain – A Journal of Neurology : http://dx.doi.org/10.1093/brain/awv002