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.

protein misfolding, prion, neurodegeneration, nicotinamide dinucleotide, neuroprotection