NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

Abstract

Abnormal protein aggregation is a feature of many neurodegenerative conditions. The NAD synthase NMNAT (nicotinamide mononucleotide adenylyltransferase) is known to protect against induced neuro-degeneration in Drosophila. Now work in mice confirms an antidegenerative action for NMNAT and also a possible mechanism: it acts as a chaperone, helping other proteins to fold. The NAD synthase NMNAT (nicotinamide mononucleotide adenylyltransferase) protects against a various forms of neurodegeneration. This paper shows that NMNAT does so by virtue of its newly discovered chaperone activity. Neurodegeneration can be triggered by genetic or environmental factors. Although the precise cause is often unknown, many neurodegenerative diseases share common features such as protein aggregation and age dependence. Recent studies in Drosophila have uncovered protective effects of NAD synthase nicotinamide mononucleotide adenylyltransferase (NMNAT) against activity-induced neurodegeneration and injury-induced axonal degeneration1,2. Here we show that NMNAT overexpression can also protect against spinocerebellar ataxia 1 (SCA1)-induced neurodegeneration, suggesting a general neuroprotective function of NMNAT. It protects against neurodegeneration partly through a proteasome-mediated pathway in a manner similar to heat-shock protein 70 (Hsp70). NMNAT displays chaperone function both in biochemical assays and cultured cells, and it shares significant structural similarity with known chaperones. Furthermore, it is upregulated in the brain upon overexpression of poly-glutamine expanded protein and recruited with the chaperone Hsp70 into protein aggregates. Our results implicate NMNAT as a stress-response protein that acts as a chaperone for neuronal maintenance and protection. Our studies provide an entry point for understanding how normal neurons maintain activity, and offer clues for the common mechanisms underlying different neurodegenerative conditions.