1. Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
2. Howard Hughes Medical Institute, Baylor College of Medicine,
3. Department of Molecular and Human Genetics, Baylor College of Medicine,
4. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA
5. These authors contributed equally to this work.
6. Present address: Department of Physiology and Green Center Division for Systems Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.

Correspondence to: R. Grace Zhai^1,2,3,5Hugo J. Bellen^2,3,4 Correspondence and requests for materials should be addressed to R.G.Z. (Email: gzhai@med.miami.edu) or H.B. (Email: hbellen@bcm.edu).

Abstract

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 degeneration^{1, 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.

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