Pharmacological chaperone for α-crystallin partially restores transparency in cataract models

Leah N. Makley; Kathryn A. McMenimen; Brian T. DeVree; Joshua W. Goldman; Brittney N. McGlasson; Ponni Rajagopal; Bryan M. Dunyak; Thomas J. McQuade; Andrea D. Thompson; Roger Sunahara; Rachel E. Klevit; Usha P. Andley; Jason E. Gestwicki

doi:10.1126/science.aac9145

Pharmacological chaperone for α-crystallin partially restores transparency in cataract models

Leah N. Makley, Kathryn A. McMenimen, Brian T. DeVree, Joshua W. Goldman, Brittney N. McGlasson, Ponni Rajagopal, Bryan M. Dunyak, Thomas J. McQuade, Andrea D. Thompson, Roger Sunahara, Rachel E. Klevit, Usha P. Andley, Jason E. Gestwicki

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

199 Scopus citations

Abstract

Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing a-crystallins.

Original language	English
Pages (from-to)	674-677
Number of pages	4
Journal	Science
Volume	350
Issue number	6261
DOIs	https://doi.org/10.1126/science.aac9145
State	Published - Nov 6 2015

Access to Document

10.1126/science.aac9145

Cite this

Makley, L. N., McMenimen, K. A., DeVree, B. T., Goldman, J. W., McGlasson, B. N., Rajagopal, P., Dunyak, B. M., McQuade, T. J., Thompson, A. D., Sunahara, R., Klevit, R. E., Andley, U. P., & Gestwicki, J. E. (2015). Pharmacological chaperone for α-crystallin partially restores transparency in cataract models. Science, 350(6261), 674-677. https://doi.org/10.1126/science.aac9145

@article{c5004c6a702f43a7b09e501c8e9341ed,

title = "Pharmacological chaperone for α-crystallin partially restores transparency in cataract models",

abstract = "Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing a-crystallins.",

author = "Makley, {Leah N.} and McMenimen, {Kathryn A.} and DeVree, {Brian T.} and Goldman, {Joshua W.} and McGlasson, {Brittney N.} and Ponni Rajagopal and Dunyak, {Bryan M.} and McQuade, {Thomas J.} and Thompson, {Andrea D.} and Roger Sunahara and Klevit, {Rachel E.} and Andley, {Usha P.} and Gestwicki, {Jason E.}",

year = "2015",

month = nov,

day = "6",

doi = "10.1126/science.aac9145",

language = "English",

volume = "350",

pages = "674--677",

journal = "Science",

issn = "0036-8075",

number = "6261",

}

TY - JOUR

T1 - Pharmacological chaperone for α-crystallin partially restores transparency in cataract models

AU - Makley, Leah N.

AU - McMenimen, Kathryn A.

AU - DeVree, Brian T.

AU - Goldman, Joshua W.

AU - McGlasson, Brittney N.

AU - Rajagopal, Ponni

AU - Dunyak, Bryan M.

AU - McQuade, Thomas J.

AU - Thompson, Andrea D.

AU - Sunahara, Roger

AU - Klevit, Rachel E.

AU - Andley, Usha P.

AU - Gestwicki, Jason E.

PY - 2015/11/6

Y1 - 2015/11/6

N2 - Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing a-crystallins.

AB - Cataracts reduce vision in 50% of individuals over 70 years of age and are a common form of blindness worldwide. Cataracts are caused when damage to the major lens crystallin proteins causes their misfolding and aggregation into insoluble amyloids. Using a thermal stability assay, we identified a class of molecules that bind α-crystallins (cryAA and cryAB) and reversed their aggregation in vitro. The most promising compound improved lens transparency in the R49C cryAA and R120G cryAB mouse models of hereditary cataract. It also partially restored protein solubility in the lenses of aged mice in vivo and in human lenses ex vivo. These findings suggest an approach to treating cataracts by stabilizing a-crystallins.

UR - http://www.scopus.com/inward/record.url?scp=84947208872&partnerID=8YFLogxK

U2 - 10.1126/science.aac9145

DO - 10.1126/science.aac9145

M3 - Article

C2 - 26542570

AN - SCOPUS:84947208872

SN - 0036-8075

VL - 350

SP - 674

EP - 677

JO - Science

JF - Science

IS - 6261

ER -

Pharmacological chaperone for α-crystallin partially restores transparency in cataract models

Abstract

Access to Document

Other files and links

Fingerprint

Cite this