Zhai RG, Cao Y, Hiesinger PR, Zhou Y, Mehta SQ, Schulze KL, Verstreken P, Bellen HJ. Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity. PLoS Biol. 2006 Nov;4(12):e416. PubMed.
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Babraham Institute
This paper indicates an intriguing, but as yet unknown, essential function of Nmnat that is distinct from NAD synthesis. The activity-independent function is required for neuronal survival under normal physiological conditions and for resistance to neurodegeneration of excessively stimulated photoreceptors, caused either by constitutive phototransduction or exposure to intense light.
These results add to a growing debate as to whether Nmnat and its mammalian isoforms can delay the degeneration of injured axons (Wallerian degeneration). The relevance of Wallerian degeneration to Alzheimer disease is described below. Nmnat1 is part of the slow Wallerian degeneration protein (Wlds), an unusual chimeric protein which delays Wallerian degeneration for 14 days or more in mice and rats and also partially protects synapses [1-3]. The same gene can delay axon degeneration in some neurodegenerative diseases where there is no physical injury, suggesting that other insults such as a block of axonal transport can trigger a similar degenerative pathway to injury [4-6]. Data from primary neuronal culture experiments suggest that Nmnat1 is sufficient for this protective activity [7,8]. In contrast, overexpression of Nmnat1 in transgenic mice at levels similar to Wlds has no protective effect at all [9]. Ultimately, the protective agent must work in vivo, both to be sure that we fully understand the mechanism and because any future therapeutic application of this knowledge will be in vivo. Interestingly, Nmnat does partially protect injured axons in Drosophila, although its efficacy remains uncertain, as so far this protective effect of Nmnat is reported only for 5 days as opposed to 30 days for Wlds [10].
Critically, Nmnat, and NAD metabolites and precursors, may have several protective functions that can alter neurodegeneration, and it is essential not to confuse these with one another. The key test for protection against Wallerian degeneration is to ask whether transected axons are preserved. Without such a test, we cannot truly say that something protects against Wallerian degeneration, because Waller himself defined this process by cutting axons [11]. However, this is not just a matter of semantics. The stringency imposed by testing for survival of injured axons for 14 days in vivo is important to prevent confusion between different pathways of degeneration and neuroprotection.
This test was not applied to the enzyme-dead Nmnat in Zhai et al. Considering that the protective function of Nmnat described here is independent of NAD synthesis activity, in contrast to protection from Wallerian degeneration where enzyme activity is required, at least in primary culture [8,9], this is an essential gap to close before we can say that enzyme-dead Nmnat protects from Wallerian degeneration.
Regarding the implications for Alzheimer disease, the importance of axon degeneration in AD is becoming more and more clear. Dystrophic axons occur in the immediate vicinity of amyloid plaques [12,13], impairing axonal transport worsens plaque deposition [14], and shifting the site of Aβ synthesis away from axons and synapses reduces the amyloid burden [15]. Whether axon degeneration in AD is Wallerian-like, as it clearly is in at least some other neurodegenerative diseases [4,5], is an important next step to clarify. If and when this can be shown, factors that delay Wallerian degeneration in vivo may have therapeutic value in AD. So far, no other gene or drug, including Nmnat, has come close to the efficacy of Wlds in doing this.
References:
Lunn ER, Perry VH, Brown MC, Rosen H, Gordon S. Absence of Wallerian Degeneration does not Hinder Regeneration in Peripheral Nerve. Eur J Neurosci. 1989;1(1):27-33. PubMed.
Mack TG, Reiner M, Beirowski B, Mi W, Emanuelli M, Wagner D, Thomson D, Gillingwater T, Court F, Conforti L, Fernando FS, Tarlton A, Andressen C, Addicks K, Magni G, Ribchester RR, Perry VH, Coleman MP. Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric gene. Nat Neurosci. 2001 Dec;4(12):1199-206. PubMed.
Gillingwater TH, Ingham CA, Parry KE, Wright AK, Haley JE, Wishart TM, Arbuthnott GW, Ribchester RR. Delayed synaptic degeneration in the CNS of Wlds mice after cortical lesion. Brain. 2006 Jun;129(Pt 6):1546-56. PubMed.
Ferri A, Sanes JR, Coleman MP, Cunningham JM, Kato AC. Inhibiting axon degeneration and synapse loss attenuates apoptosis and disease progression in a mouse model of motoneuron disease. Curr Biol. 2003 Apr 15;13(8):669-73. PubMed.
Samsam M, Mi W, Wessig C, Zielasek J, Toyka KV, Coleman MP, Martini R. The Wlds mutation delays robust loss of motor and sensory axons in a genetic model for myelin-related axonopathy. J Neurosci. 2003 Apr 1;23(7):2833-9. PubMed.
Mi W, Beirowski B, Gillingwater TH, Adalbert R, Wagner D, Grumme D, Osaka H, Conforti L, Arnhold S, Addicks K, Wada K, Ribchester RR, Coleman MP. The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice. Brain. 2005 Feb;128(Pt 2):405-16. PubMed.
Wang J, Zhai Q, Chen Y, Lin E, Gu W, McBurney MW, He Z. A local mechanism mediates NAD-dependent protection of axon degeneration. J Cell Biol. 2005 Aug 1;170(3):349-55. PubMed.
Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004 Aug 13;305(5686):1010-3. PubMed.
Conforti L, Fang G, Beirowski B, Wang MS, Sorci L, Asress S, Adalbert R, Silva A, Bridge K, Huang XP, Magni G, Glass JD, Coleman MP. NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration. Cell Death Differ. 2007 Jan;14(1):116-27. PubMed.
Macdonald JM, Beach MG, Porpiglia E, Sheehan AE, Watts RJ, Freeman MR. The Drosophila cell corpse engulfment receptor Draper mediates glial clearance of severed axons. Neuron. 2006 Jun 15;50(6):869-81. PubMed.
Waller A. Experiments on the section of glossopharyngeal and hypoglossal nerves of the frog and observations uf the alternatives produced thereby in the structure of their primitive fibres. Philos Trans R Soc Lond B Biol Sci 1850. 140:423-429.
Tsai J, Grutzendler J, Duff K, Gan WB. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat Neurosci. 2004 Nov;7(11):1181-3. PubMed.
Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT. Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci. 2005 Aug 3;25(31):7278-87. PubMed.
Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25;307(5713):1282-8. PubMed.
Lee EB, Zhang B, Liu K, Greenbaum EA, Doms RW, Trojanowski JQ, Lee VM. BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J Cell Biol. 2005 Jan 17;168(2):291-302. PubMed.
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