Scripps Institute. US: Scientists from the Florida campus of The Scripps Research Institute
(TSRI) 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, published recently in the journal Brain,
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.”
Failure and Rescue of Brain Cells
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.”
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.
New Grant to Support Further Research
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.
Lasmézas and Louis Scampavia, a TSRI associate professor of molecular
therapeutics, will be co-principal investigators for the new three-year
study, whose team will also include Tom Bannister, a TSRI associate
scientific director at Scripps Florida’s Translational Research
Institute.
The scientists have developed several primary tests for compounds
that could restore NAD+ and plan to begin those tests at Scripps
Florida’s High Throughput Screening facility.
Since it was established in 2005, the Scripps Florida High Throughput
Screening facility has screened more than 200 targets in more than 235
industrial and academic collaborations—several of these collaborations
have produced successful clinical trial candidates. The drug discovery
facility is currently capable of routinely screens one quarter of a
million compounds in a single day.
In addition to Zhou and Lasmézas, other authors of the study,
“Neuronal Death Induced by Misfolded Prion Protein Is Due To NAD+
Depletion and Can Be Relieved In Vitro And In Vivo by
NAD+ Replenishment,” include Gregory Ottenberg, Gian Franco Sferrazza,
Christopher Hubbs, Mohammad Fallahi, Gavin Rumbaugh and Alicia F.
Brantley of TSRI. The work was supported by TSRI and by the National
Institutes of Health (RNS081519).
The number of the new NINDS grant is 1R01NS085223.