NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration

Rong G Zhai, Fangliang Zhang, P. Robin Hiesinger, Yu Cao, Claire M. Haueter, Hugo J. Bellen

Research output: Contribution to journalArticle

134 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)887-891
Number of pages5
JournalNature
Volume452
Issue number7189
DOIs
StatePublished - Apr 17 2008

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Nicotinamide-Nucleotide Adenylyltransferase
HSP70 Heat-Shock Proteins
Spinocerebellar Ataxias
Proteasome Endopeptidase Complex
Heat-Shock Proteins
Neurodegenerative Diseases
Drosophila
Cultured Cells
Proteins
Maintenance
NAD+ synthase
Neurons
Wounds and Injuries
Brain

ASJC Scopus subject areas

  • General

Cite this

Zhai, R. G., Zhang, F., Hiesinger, P. R., Cao, Y., Haueter, C. M., & Bellen, H. J. (2008). NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature, 452(7189), 887-891. https://doi.org/10.1038/nature06721

NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. / Zhai, Rong G; Zhang, Fangliang; Hiesinger, P. Robin; Cao, Yu; Haueter, Claire M.; Bellen, Hugo J.

In: Nature, Vol. 452, No. 7189, 17.04.2008, p. 887-891.

Research output: Contribution to journalArticle

Zhai, RG, Zhang, F, Hiesinger, PR, Cao, Y, Haueter, CM & Bellen, HJ 2008, 'NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration', Nature, vol. 452, no. 7189, pp. 887-891. https://doi.org/10.1038/nature06721
Zhai, Rong G ; Zhang, Fangliang ; Hiesinger, P. Robin ; Cao, Yu ; Haueter, Claire M. ; Bellen, Hugo J. / NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. In: Nature. 2008 ; Vol. 452, No. 7189. pp. 887-891.
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