Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2
The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are asso...
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Format: | Article |
Language: | English |
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Elsevier
2021-05-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996121000267 |
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doaj-2f7f6191fe64476496d37d1941f144a0 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jennifer Ngolab Saranya Canchi Suhail Rasool Abderrahman Elmaarouf Kimberly Thomas Floyd Sarsoza Jennifer Grundman Michael Mante Jazmin Florio Nimisha Nandankar Shaina Korouri Wagner Zago Eliezer Masliah Robert A. Rissman |
spellingShingle |
Jennifer Ngolab Saranya Canchi Suhail Rasool Abderrahman Elmaarouf Kimberly Thomas Floyd Sarsoza Jennifer Grundman Michael Mante Jazmin Florio Nimisha Nandankar Shaina Korouri Wagner Zago Eliezer Masliah Robert A. Rissman Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2 Neurobiology of Disease Retina Tau 3 repeat tau Retinopathy Alzheimer's, tauopathy |
author_facet |
Jennifer Ngolab Saranya Canchi Suhail Rasool Abderrahman Elmaarouf Kimberly Thomas Floyd Sarsoza Jennifer Grundman Michael Mante Jazmin Florio Nimisha Nandankar Shaina Korouri Wagner Zago Eliezer Masliah Robert A. Rissman |
author_sort |
Jennifer Ngolab |
title |
Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2 |
title_short |
Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2 |
title_full |
Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2 |
title_fullStr |
Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2 |
title_full_unstemmed |
Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2 |
title_sort |
mutant three-repeat tau expression initiates retinal ganglion cell death through caspase-2 |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2021-05-01 |
description |
The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick's Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma. |
topic |
Retina Tau 3 repeat tau Retinopathy Alzheimer's, tauopathy |
url |
http://www.sciencedirect.com/science/article/pii/S0969996121000267 |
work_keys_str_mv |
AT jenniferngolab mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT saranyacanchi mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT suhailrasool mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT abderrahmanelmaarouf mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT kimberlythomas mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT floydsarsoza mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT jennifergrundman mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT michaelmante mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT jazminflorio mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT nimishanandankar mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT shainakorouri mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT wagnerzago mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT eliezermasliah mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 AT robertarissman mutantthreerepeattauexpressioninitiatesretinalganglioncelldeaththroughcaspase2 |
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1724209240191533056 |
spelling |
doaj-2f7f6191fe64476496d37d1941f144a02021-03-22T08:43:10ZengElsevierNeurobiology of Disease1095-953X2021-05-01152105277Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2Jennifer Ngolab0Saranya Canchi1Suhail Rasool2Abderrahman Elmaarouf3Kimberly Thomas4Floyd Sarsoza5Jennifer Grundman6Michael Mante7Jazmin Florio8Nimisha Nandankar9Shaina Korouri10Wagner Zago11Eliezer Masliah12Robert A. Rissman13Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Amydis Inc, San Diego, CA 92121, United States of AmericaProthena Biosciences, South San Francisco, CA 94080, United States of AmericaProthena Biosciences, South San Francisco, CA 94080, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of AmericaProthena Biosciences, South San Francisco, CA 94080, United States of AmericaDivision of Neuroscience and Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD 20892, United States of AmericaDepartment of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of America; Corresponding author at: Department of Neurosciences, UCSD School of Medicine, 9500 Gilman Drive, MTF 309, M/C 0624, La Jolla, CA 92093-0624, United States of America.The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick's Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma.http://www.sciencedirect.com/science/article/pii/S0969996121000267RetinaTau3 repeat tauRetinopathyAlzheimer's, tauopathy |