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Brain. 2015 Apr;138(Pt 4):992-1008. doi: 10.1093/brain/awv002. Epub 2015 Feb 11.

Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment.

Author information

1
1 Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
2
2 Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
3
3 Informatics Core, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
4
4 Behaviour Core, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
5
1 Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA lasmezas@scripps.edu.

Abstract

The mechanisms of neuronal death in protein misfolding neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases are poorly understood. We used a highly toxic misfolded prion protein (TPrP) model to understand neurotoxicity induced by prion protein misfolding. We show that abnormal autophagy activation and neuronal demise is due to severe, neuron-specific, nicotinamide adenine dinucleotide (NAD(+)) depletion. Toxic prion protein-exposed neuronal cells exhibit dramatic reductions of intracellular NAD(+) followed by decreased ATP production, and are completely rescued by treatment with NAD(+) or its precursor nicotinamide because of restoration of physiological NAD(+) levels. Toxic prion protein-induced NAD(+) depletion results from PARP1-independent excessive protein ADP-ribosylations. In vivo, toxic prion protein-induced degeneration of hippocampal neurons is prevented dose-dependently by intracerebral injection of NAD(+). Intranasal NAD(+) treatment of prion-infected sick mice significantly improves activity and delays motor impairment. Our study reveals NAD(+) starvation as a novel mechanism of autophagy activation and neurodegeneration induced by a misfolded amyloidogenic protein. We propose the development of NAD(+) replenishment strategies for neuroprotection in prion diseases and possibly other protein misfolding neurodegenerative diseases.

KEYWORDS:

neurodegeneration; neuroprotection; nicotinamide dinucleotide; prion; protein misfolding

PMID:
25678560
PMCID:
PMC4840455
DOI:
10.1093/brain/awv002
[Indexed for MEDLINE]
Free PMC Article

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