Axonal Protection by Nmnat3 Overexpression with Involvement of Autophagy in Optic Nerve Degeneration

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2013 Oct 19

PMID 24136224

Citations 60

Authors

Y Kitaoka

Y Munemasa

K Kojima

A Hirano

S Ueno

H Takagi

Affiliations

Soon will be listed here.

Abstract

Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the crucial role of nicotinamide mononucleotide adenylyltransferase (Nmnat) 1, 2, and 3 in axonal protection. In this study, Nmnat3 immunoreactivity was observed inside axons in the optic nerve. Overexpression of Nmnat3 exerts axonal protection against tumor necrosis factor-induced and intraocular pressure (IOP) elevation-induced optic nerve degeneration. Immunoblot analysis showed that both p62 and microtubule-associated protein light chain 3 (LC3)-II were upregulated in the optic nerve after IOP elevation. Nmnat3 transfection decreased p62 and increased LC3-II in the optic nerve both with and without experimental glaucoma. Electron microscopy showed the existence of autophagic vacuoles in optic nerve axons in the glaucoma, glaucoma+Nmnat3 transfection, and glaucoma+rapamycin groups, although preserved myelin and microtubule structures were noted in the glaucoma+Nmnat3 transfection and glaucoma+rapamycin groups. The axonal-protective effect of Nmnat3 was inhibited by 3-methyladenine, whereas rapamycin exerted axonal protection after IOP elevation. We found that p62 was present in the mitochondria and confirmed substantial colocalization of mitochondrial Nmnat3 and p62 in starved retinal ganglion cell (RGC)-5 cells. Nmnat3 transfection decreased p62 and increased autophagic flux in RGC-5 cells. These results suggest that the axonal-protective effect of Nmnat3 may be involved in autophagy machinery, and that modulation of Nmnat3 and autophagy may lead to potential strategies against degenerative optic nerve disease.

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References

Press C, Milbrandt J . Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress. J Neurosci. 2008; 28(19):4861-71. PMC: 2678678. DOI: 10.1523/JNEUROSCI.0525-08.2008. View

Libby R, Li Y, Savinova O, Barter J, Smith R, Nickells R . Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet. 2005; 1(1):17-26. PMC: 1183523. DOI: 10.1371/journal.pgen.0010004. View

Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T, She H . Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci. 2006; 26(49):12633-41. PMC: 6674838. DOI: 10.1523/JNEUROSCI.2801-06.2006. View

Yan T, Feng Y, Zheng J, Ge X, Zhang Y, Wu D . Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity. Neurochem Int. 2009; 56(1):101-6. DOI: 10.1016/j.neuint.2009.09.007. View

Barron M, Griffiths P, Turnbull D, Bates D, Nichols P . The distributions of mitochondria and sodium channels reflect the specific energy requirements and conduction properties of the human optic nerve head. Br J Ophthalmol. 2004; 88(2):286-90. PMC: 1771975. DOI: 10.1136/bjo.2003.027664. View

Araki T, Sasaki Y, Milbrandt J . Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science. 2004; 305(5686):1010-3. DOI: 10.1126/science.1098014. View

Gilley J, Coleman M . Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons. PLoS Biol. 2010; 8(1):e1000300. PMC: 2811159. DOI: 10.1371/journal.pbio.1000300. View

Park H, Kim J, Park C . Activation of autophagy induces retinal ganglion cell death in a chronic hypertensive glaucoma model. Cell Death Dis. 2012; 3:e290. PMC: 3358006. DOI: 10.1038/cddis.2012.26. View

Tanabe F, Yone K, Kawabata N, Sakakima H, Matsuda F, Ishidou Y . Accumulation of p62 in degenerated spinal cord under chronic mechanical compression: functional analysis of p62 and autophagy in hypoxic neuronal cells. Autophagy. 2011; 7(12):1462-71. PMC: 3288020. DOI: 10.4161/auto.7.12.17892. View

10.

Johansen T, Lamark T . Selective autophagy mediated by autophagic adapter proteins. Autophagy. 2010; 7(3):279-96. PMC: 3060413. DOI: 10.4161/auto.7.3.14487. View

11.

Munemasa Y, Kwong J, Caprioli J, Piri N . The role of alphaA- and alphaB-crystallins in the survival of retinal ganglion cells after optic nerve axotomy. Invest Ophthalmol Vis Sci. 2009; 50(8):3869-75. DOI: 10.1167/iovs.08-3138. View

12.

Sasaki Y, Araki T, Milbrandt J . Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci. 2006; 26(33):8484-91. PMC: 6674352. DOI: 10.1523/JNEUROSCI.2320-06.2006. View

13.

Sagot Y, Dubois-Dauphin M, Tan S, de Bilbao F, Aebischer P, Martinou J . Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. J Neurosci. 1995; 15(11):7727-33. PMC: 6578059. View

14.

Munemasa Y, Kitaoka Y, Kuribayashi J, Ueno S . Modulation of mitochondria in the axon and soma of retinal ganglion cells in a rat glaucoma model. J Neurochem. 2010; 115(6):1508-19. DOI: 10.1111/j.1471-4159.2010.07057.x. View

15.

Xu H, Wu D, Gu J, Ge J, Wu J, Han R . The pro-survival role of autophagy depends on Bcl-2 under nutrition stress conditions. PLoS One. 2013; 8(5):e63232. PMC: 3643928. DOI: 10.1371/journal.pone.0063232. View

16.

Tezel G, Li L, Patil R, Wax M . TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. Invest Ophthalmol Vis Sci. 2001; 42(8):1787-94. View

17.

Kitaoka Y, Munemasa Y, Hayashi Y, Kuribayashi J, Koseki N, Kojima K . Axonal protection by 17β-estradiol through thioredoxin-1 in tumor necrosis factor-induced optic neuropathy. Endocrinology. 2011; 152(7):2775-85. DOI: 10.1210/en.2011-0046. View

18.

Zhang Y, Gong J, Xing T, Zheng S, Ding W . Autophagy protein p62/SQSTM1 is involved in HAMLET-induced cell death by modulating apotosis in U87MG cells. Cell Death Dis. 2013; 4:e550. PMC: 3615731. DOI: 10.1038/cddis.2013.77. View

19.

Kitaoka Y, Kitaoka Y, Kwong J, Ross-Cisneros F, Wang J, Tsai R . TNF-alpha-induced optic nerve degeneration and nuclear factor-kappaB p65. Invest Ophthalmol Vis Sci. 2006; 47(4):1448-57. DOI: 10.1167/iovs.05-0299. View

20.

Komatsu M, Waguri S, Koike M, Sou Y, Ueno T, Hara T . Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell. 2007; 131(6):1149-63. DOI: 10.1016/j.cell.2007.10.035. View