Misfolded proteins, which accumulate in neurodegenerative diseases such as ALS, Alzheimer’s and Parkinson’s disease, can trigger misfolding and aggregation of their non-mutant protein counterparts in a prion-like manner. In ALS, both TDP-43 and SOD1 demonstrate prion-like properties (see Feb 2014 news story; Nov 2013 news story) and may contribute to the characteristic spreading of neurodegeneration in the central nervous system. A new study published February 11 in Brain reveals a mechanism underlying toxicity of prion proteins that may also apply to other protein misfolding neurodegenerative diseases. Researchers led by Corinne Lasmézas and colleagues at the the Scripps Research Institute in Jupiter, Florida demonstrate that in both neuronal cultures and in mouse models infected with a toxic misfolded prion protein (TPrP), depletion of nicotinamide adenine dinucleotide (NAD+), a metabolite necessary for energy production, drives neuronal death. TPrP-induced neuronal death could be prevented by NAD+ supplementation. The team is now developing screening assays for compounds that can restore NAD+ levels and may have therapeutic promise for diseases linked to protein misfolding.
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Zhou M, Ottenberg G, Sferrazza GF, Hubbs C, Fallahi M, Rumbaugh G, Brantley AF, Lasmézas CI. Neuronal death induced by misfolded prion protein is due to NAD+ depletion and can be relieved in vitro and in vivo by NAD+ replenishment. Brain. 2015 Feb 11; [PubMed].