Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Yiqing Li; Lukas Andereggen; Kenya Yuki; Kumiko Omura; Yuqin Yin; Hui Ya Gilbert; Burcu Erdogan; Maria S. Asdourian; Christine Shrock; Silmara De Lima; Ulf Peter Apfel; Yehong Zhuo; Michal Hershfinkel; Stephen J. Lippard; Paul A. Rosenberg; Larry Benowitz

doi:10.1073/pnas.1616811114

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

Yiqing Li, Lukas Andereggen, Kenya Yuki, Kumiko Omura, Yuqin Yin, Hui Ya Gilbert, Burcu Erdogan, Maria S. Asdourian, Christine Shrock, Silmara De Lima, Ulf Peter Apfel, Yehong Zhuo, Michal Hershfinkel, Stephen J. Lippard, Paul A. Rosenberg, Larry Benowitz

Department of Physiology and Cell Biology

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

Abstract

Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die.Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn²⁺) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn²⁺ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn²⁺ accumulation in amacrine cell processes involves the Zn²⁺ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn²⁺ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn²⁺ chelation extends for several days after nerve injury. These results show that retinal Zn²⁺ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn²⁺ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

Original language	English
Pages (from-to)	E209-E218
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	2
DOIs	https://doi.org/10.1073/pnas.1616811114
State	Published - 10 Jan 2017

Keywords

Amacrine cell
Cell death
Chelation
Exocytosis
Neuroprotection

ASJC Scopus subject areas

General

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10.1073/pnas.1616811114

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Li, Y., Andereggen, L., Yuki, K., Omura, K., Yin, Y., Gilbert, H. Y., Erdogan, B., Asdourian, M. S., Shrock, C., De Lima, S., Apfel, U. P., Zhuo, Y., Hershfinkel, M., Lippard, S. J., Rosenberg, P. A., & Benowitz, L. (2017). Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. Proceedings of the National Academy of Sciences of the United States of America, 114(2), E209-E218. https://doi.org/10.1073/pnas.1616811114

@article{0fae4281f16146859457bfc7eb09abb9,

title = "Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration",

abstract = "Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die.Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn2+) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn2+ accumulation in amacrine cell processes involves the Zn2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn2+ chelation extends for several days after nerve injury. These results show that retinal Zn2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.",

keywords = "Amacrine cell, Cell death, Chelation, Exocytosis, Neuroprotection",

author = "Yiqing Li and Lukas Andereggen and Kenya Yuki and Kumiko Omura and Yuqin Yin and Gilbert, {Hui Ya} and Burcu Erdogan and Asdourian, {Maria S.} and Christine Shrock and {De Lima}, Silmara and Apfel, {Ulf Peter} and Yehong Zhuo and Michal Hershfinkel and Lippard, {Stephen J.} and Rosenberg, {Paul A.} and Larry Benowitz",

note = "Funding Information: This work was supported in part by National Eye Institute Grant 1 R01 EY024481 (to P.A.R. and L.B.); National Institute of Neurological Diseases and Stroke Grant R01NS066019 (to P.A.R.); National Institute of Mental Health Grant R21MH104318 (to P.A.R.); US Department of Defense Grant CDMRP DM102446 (to L.B.); the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (L.B.); National Institute of General Medical Sciences Grant GM 065519 (to S.J.L.); China Scholarship Council Grant 2010638086 (to Y.L.); Swiss National Science Foundation Grants PBBEB-146099 and PBBEB-155299 (to L.A.);",

year = "2017",

month = jan,

day = "10",

doi = "10.1073/pnas.1616811114",

language = "English",

volume = "114",

pages = "E209--E218",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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Li, Y, Andereggen, L, Yuki, K, Omura, K, Yin, Y, Gilbert, HY, Erdogan, B, Asdourian, MS, Shrock, C, De Lima, S, Apfel, UP, Zhuo, Y, Hershfinkel, M, Lippard, SJ, Rosenberg, PA & Benowitz, L 2017, 'Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 2, pp. E209-E218. https://doi.org/10.1073/pnas.1616811114

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration. / Li, Yiqing; Andereggen, Lukas; Yuki, Kenya et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 2, 10.01.2017, p. E209-E218.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

AU - Li, Yiqing

AU - Andereggen, Lukas

AU - Yuki, Kenya

AU - Omura, Kumiko

AU - Yin, Yuqin

AU - Gilbert, Hui Ya

AU - Erdogan, Burcu

AU - Asdourian, Maria S.

AU - Shrock, Christine

AU - De Lima, Silmara

AU - Apfel, Ulf Peter

AU - Zhuo, Yehong

AU - Hershfinkel, Michal

AU - Lippard, Stephen J.

AU - Rosenberg, Paul A.

AU - Benowitz, Larry

N1 - Funding Information: This work was supported in part by National Eye Institute Grant 1 R01 EY024481 (to P.A.R. and L.B.); National Institute of Neurological Diseases and Stroke Grant R01NS066019 (to P.A.R.); National Institute of Mental Health Grant R21MH104318 (to P.A.R.); US Department of Defense Grant CDMRP DM102446 (to L.B.); the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (L.B.); National Institute of General Medical Sciences Grant GM 065519 (to S.J.L.); China Scholarship Council Grant 2010638086 (to Y.L.); Swiss National Science Foundation Grants PBBEB-146099 and PBBEB-155299 (to L.A.);

PY - 2017/1/10

Y1 - 2017/1/10

N2 - Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die.Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn2+) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn2+ accumulation in amacrine cell processes involves the Zn2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn2+ chelation extends for several days after nerve injury. These results show that retinal Zn2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

AB - Retinal ganglion cells (RGCs), the projection neurons of the eye, cannot regenerate their axons once the optic nerve has been injured and soon begin to die.Whereas RGC death and regenerative failure are widely viewed as being cell-autonomous or influenced by various types of glia, we report here that the dysregulation of mobile zinc (Zn2+) in retinal interneurons is a primary factor. Within an hour after the optic nerve is injured, Zn2+ increases several-fold in retinal amacrine cell processes and continues to rise over the first day, then transfers slowly to RGCs via vesicular release. Zn2+ accumulation in amacrine cell processes involves the Zn2+ transporter protein ZnT-3, and deletion of slc30a3, the gene encoding ZnT-3, promotes RGC survival and axon regeneration. Intravitreal injection of Zn2+ chelators enables many RGCs to survive for months after nerve injury and regenerate axons, and enhances the prosurvival and regenerative effects of deleting the gene for phosphatase and tensin homolog (pten). Importantly, the therapeutic window for Zn2+ chelation extends for several days after nerve injury. These results show that retinal Zn2+ dysregulation is a major factor limiting the survival and regenerative capacity of injured RGCs, and point to Zn2+ chelation as a strategy to promote long-term RGC protection and enhance axon regeneration.

KW - Amacrine cell

KW - Cell death

KW - Chelation

KW - Exocytosis

KW - Neuroprotection

UR - http://www.scopus.com/inward/record.url?scp=85009373477&partnerID=8YFLogxK

U2 - 10.1073/pnas.1616811114

DO - 10.1073/pnas.1616811114

M3 - Article

C2 - 28049831

AN - SCOPUS:85009373477

SN - 0027-8424

VL - 114

SP - E209-E218

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 2

ER -

Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration

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