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

作者：Zhou Minghai; Ottenberg Gregory; Sferrezza Gian Franco; Hubbs Christopher; Fallahi Mohammad; Rumbaugh Gavin; Brantley Alicia F; Lasmezas Corinne I^*

来源：Brain, 2015, 138(4): 992-1008.

DOI：10.1093/brain/awv002

• protein misfolding
• prion
• neurodegeneration
• nicotinamide dinucleotide
• neuroprotection

The mechanisms by which misfolded proteins trigger neurodegeneration remain unclear. Zhou et al. show that the misfolded prion protein TPrP triggers abnormal autophagy activation and neuronal death via NAD + depletion resulting from excessive PARP1-independent ADP-ribosylation. NAD + replenishment rescues prion protein-damaged neurons, suggesting neuroprotective potential in prion-mediated neurodegenerative diseases.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.

• 出版日期2015-4-1