title: Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment.
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.
authors: 1 Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Minghai
authors: M
authors: Zhou
authors: 1 Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Gregory
authors: G
authors: Ottenberg
authors: 1 Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Gian Franco
authors: GF
authors: Sferrazza
authors: 2 Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Christopher
authors: C
authors: Hubbs
authors: 3 Informatics Core, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Mohammad
authors: M
authors: Fallahi
authors: 2 Department of Neuroscience, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Gavin
authors: G
authors: Rumbaugh
authors: 4 Behaviour Core, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors: Alicia F
authors: AF
authors: Brantley
authors: 1 Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA lasmezas@scripps.edu.
authors: Corinne I
authors: CI
authors: Lasmézas
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000172:deficiency* / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017096:Prion Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000633:toxicity*; D017510:Protein Folding / Q000187:drug effects
chemical_list: D011328:Prions; D009243:NAD
keywords: neurodegeneration; neuroprotection; nicotinamide dinucleotide; prion; protein misfolding