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NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration.

Nature | Apr 17, 2008

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.

Pubmed ID: 18344983 RIS Download

Mesh terms: Amide Synthases | Animals | Ataxin-1 | Ataxins | Brain | COS Cells | Cercopithecus aethiops | Disease Models, Animal | Drosophila | Drosophila Proteins | HSP70 Heat-Shock Proteins | Humans | Molecular Chaperones | Nerve Degeneration | Nerve Tissue Proteins | Neurodegenerative Diseases | Nicotinamide-Nucleotide Adenylyltransferase | Nuclear Proteins | Spinocerebellar Ataxias

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Associated grants

  • Agency: Howard Hughes Medical Institute, Id: P30 HD024064
  • Agency: NICHD NIH HHS, Id: P30 HD024064-20
  • Agency: NICHD NIH HHS, Id:

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